Oligosaccharide derivative

ABSTRACT

Compounds having the formula (I): 
                         
wherein A represents a group such as a cyclic group, R 1  and R 2  represent groups such as alkyl groups or hydroxymethyl groups, and n represents 1 or 2, or pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof have superior activity and stability, and are useful for the treatment and/or prevention of diabetes mellitus, or the like.

This is a divisional application of prior application U.S. Ser. No.11/193,655, filed Jul. 28, 2005, now U.S. Pat. No. 7,361,744 to whichpriority under 35 U.S.C. §120 is claimed, which is a continuation ofInternational Application No. PCT/JP2004/000879, filed Jan. 29, 2004,which claims the benefit of the Japanese Patent JP2003/022800, filed onJan. 30, 2003, the disclosures of which are all incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a novel oligosaccharide derivative, itspharmacologically acceptable salts and its pharmacologically acceptableesters.

The present invention also relates to an oligosaccharide derivativehaving actions including α-amylase inhibitory action, blood glucoselowering action and lipid lowering action, its pharmacologicallyacceptable salts and its pharmacologically acceptable esters.

Moreover, the present invention relates to a therapeutic drug and/orpreventive drug for a disease such as, hyperglycemia, post prandialhyperglycemia, impaired glucose tolerance (IGT), diabetes mellitus,obesity, hyperlipemia, fatty liver, hepatomegaly, diabeticcomplications, neuropathy, arteriosclerosis, cataract or diabeticnephropathy (and preferably a therapeutic drug and/or preventive drugfor hyperglycemia or diabetes mellitus) containing as its activeingredient an oligosaccharide derivative, its pharmacologicallyacceptable salts or its pharmacologically acceptable esters.

Moreover, the present invention relates to a preventive drug ortherapeutic drug for the aforementioned diseases containing as itsactive ingredient the aforementioned compound, a composition forpreventing or treating the aforementioned diseases containing as itsactive ingredient the aforementioned compound, the use of theaforementioned compound to produce a pharmaceutical for preventing ortreating the aforementioned diseases, or a prevention or treatmentmethod for the aforementioned diseases in which a pharmacologicallyeffective amount of the aforementioned compound is administered to amammal (and preferably to a human).

BACKGROUND ART

In the past, digestive enzyme inhibitors such as Basen (TakedaPharmaceutical), containing voglibose, and Glucobay (Bayer), containingacarbose, have actually been used clinically as effective therapeuticdrugs for hyperglycemia. However, since both compounds inhibitα-glucosidase, they have the disadvantages of causing adverse sideeffects such as abdominal distention, flatulence, increased abdominalwind, soft stools, diarrhea and abdominal pain. Moreover, they have alsobeen reported to cause liver function disorders.

On the other hand, effects causing inhibition of the absorption ofnutrients are known to be obtainable by inhibiting not onlyα-glucosidase, but α-amylase as well, and compounds are known that lowerblood glucose levels without causing the aforementioned adverse sideeffects unique to α-glucosidase inhibitors. However, the α-amylaseactivity of these compounds is weak, and there are no compounds knownthat have adequate α-amylase inhibitory activity.

Compounds having a partial structure (sugar derivative) that is incommon with the oligosaccharide derivative of the present invention thatdemonstrate α-amylase inhibitory activity have been disclosed (see, forexample, International Publication WO 00/50434 and InternationalPublication WO 01/94367). However, these compounds differ from thecompound of the present invention in that they are required to have adeoxynojirimycin backbone or a hexahydro-3,5,6-trihydroxy-1H-azepinebackbone.

DISCLOSURE OF THE INVENTION

α-amylase inhibitors are required to be resistant to degradation in thedigestive tract (and particularly the small intestine) and demonstratestable action. However, since previously reported α-amylase inhibitorscannot be said to demonstrate adequate stability in the small intestine,there is a possibility that they cannot demonstrate adequatepharmacological effects stably. In addition, this instability in thedigestive tract (and particularly the small intestine) results in therisk of having some form of effect on liver function resulting fromabsorption of their degradation products.

Therefore, the inventors of the present invention conducted extensiveresearch for the purpose of developing a therapeutic drug and/orpreventive drug for diseases such as hyperglycemia and diabetes mellitusthat has superior α-amylase inhibitory activity and high stability, andfound that a novel oligosaccharide derivative has superior α-amylaseinhibitory action, blood glucose lowering action and lipid loweringaction, improves diseases such as hyperglycemia, post prandialhyperglycemia, hyperglycemia, impaired glucose tolerance (IGT), diabetesmellitus, obesity, hyperlipemia, fatty liver, hepatomegaly, diabeticcomplications, neuropathy, arteriosclerosis, cataract and diabeticnephropathy, and has high stability, thereby leading to completion ofthe present invention.

Namely, the present invention provides an oligosaccharide derivative,its pharmacologically acceptable salts and its pharmacologicallyacceptable esters, which are useful as therapeutic drugs or preventivedrugs for diseases such as hyperglycemia, post prandial hyperglycemia,impaired glucose tolerance (IGT), diabetes mellitus, obesity,hyperlipemia, fatty liver, hepatomegaly, diabetic complications (such asretinopathy, nephropathy and neuropathy), neuropathy, arteriosclerosis,cataract and diabetic nephropathy.

The present invention relates to a compound represented by the followinggeneral formula (I):

(wherein A represents the following general formula (A1), (A2) or (A3):

R¹ and R² may be the same or different and each represent a C1-C6 alkylgroup, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6 haloalkylgroup, R³, R⁴, R⁵ and R⁶ may be the same or different and each representa C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6haloalkyl group, amino group (which amino group may be substituted withone or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl groups), hydroxylgroup, hydrogen atom or halogen atom, R⁷ represents a C1-C6 alkyl group,C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6 haloalkyl group,hydroxyl group or hydrogen atom, and n represents an integer of 1 or 2),its pharmacologically acceptable salts or its pharmacologicallyacceptable esters.

In the present invention, a “C1-C3 alkyl group” refers to a linear orbranched alkyl group having 1 to 3 carbon atoms, examples of whichinclude methyl, ethyl, n-propyl and isopropyl groups. In R¹, R², R³, R⁴,R⁵ and R⁶, the C1-C3 alkyl group is preferably a methyl group.

In the present invention, a “C1-C6 alkyl group” refers to a linear orbranched alkyl group having 1 to 6 carbon atoms, examples of whichinclude the groups indicated as examples of the aforementioned “C1-C3alkyl group” as well as n-butyl, isobutyl, s-butyl, tert-butyl,n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl,isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutylgroups. In the substituents of R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and the aminogroup of R³, R⁴, R⁵ and R⁶, the C1-C6 alkyl group is preferably an alkylgroup having 1 to 3 carbon atoms, and most preferably a methyl group.

In the present invention, a “halogen atom” refers to a fluorine atom,chlorine atom, bromine atom or iodine atom, and is preferably a fluorineatom in R³, R⁴, R⁵, R⁶, R⁸, R⁹ and R¹¹.

In the present invention, a “C1-C3 haloalkyl group” or “C1-C6 haloalkylgroup” respectively refer to groups in which the aforementioned “C1-C3alkyl group” or “C1-C6 alkyl group” is substituted with theaforementioned “halogen atom(s)”. Examples of the “C1-C3 haloalkylgroup” include trifluoromethyl, trichloromethyl, difluoromethyl,dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl,2-iodoethyl, 3-chloropropyl and 2,2-dibromoethyl groups, and it ispreferably a fluoromethyl group in R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹⁰.Examples of the “C1-C6 haloalkyl group” include the aforementionedexamples of the “C1-C3 haloalkyl group” as well as 4-iodobutyl,4-fluorobutyl, 4-chlorobutyl, 5-iodopentyl, 5-fluoropentyl,5-chloropentyl, 6-iodohexyl, 6-fluorohexyl and 6-chlorohexyl groups, andit is preferably a C1-C3 haloalkyl group and more preferably afluoromethyl group in R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹⁰.

In the present invention, a “C1-C3 hydroxyalkyl group” or “C1-C6hydroxyalkyl group” respectively refers to a group in which theaforementioned “C1-C3 alkyl group” or “C1-C6 alkyl group” is substitutedwith a hydroxyl group. Examples of the “C1-C3 hydroxyalkyl group”include hydroxymethyl, hydroxyethyl and hydroxypropyl groups, and it ispreferably a hydroxymethyl group in R³, R⁴, R⁵, R⁶, R⁷, R¹⁰ and R¹¹.Examples of the “C1-C6 hydroxyalkyl group” include the aforementionedexamples of the “C1-C3 hydroxyalkyl group” as well as hydroxybutyl,hydroxypentyl and hydroxyhexyl groups, and it is preferably a C1-C3hydroxyalkyl group, and more preferably a hydroxymethyl group, in R³,R⁴, R⁵, R⁶, R⁷, R¹⁰ and R¹¹.

In the present invention, a “C1-C3 alkoxy group” or “C1-C6 alkoxy group”respectively refers to a group in which a “C1-C3 alkyl group” or “C1-C6alkyl group” is bonded to an oxygen atom. Examples of the “C1-C3 alkoxygroup” include methoxy, ethoxy, n-propoxy and isopropoxy groups.Examples of the “C1-C6 alkoxy group” include the aforementioned examplesof a “C1-C3 alkoxy group” as well as n-butoxy, isobutoxy, s-butoxy,tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy,n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy groups,and it is preferably a C1-C3 alkoxy group, and more preferably a methoxygroup, in R³, R⁴, R⁵, R⁶ and R⁷.

In the present invention, a “C1-C3 alkoxymethyl group” or “C1-C6alkoxymethyl group” respectively refers to a group in which theaforementioned “C1-C3 alkoxy group” or “C1-C6 alkoxy group” is bonded toa methyl group. Examples of the “C1-C3 alkoxymethyl group” includemethoxymethyl, ethoxymethyl, n-propoxymethyl and isopropoxymethylgroups, and it is preferably a methoxymethyl group in R¹ and R².Examples of a “C1-C6 alkoxymethyl group” include the aforementionedexamples of the “C1-C3 alkoxymethyl group” as well as n-butoxymethyl,isobutoxymethyl, s-butoxymethyl, tert-butoxymethyl, n-pentoxymethyl,isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl,n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methylpentoxymethyl,2-methylpentoxymethyl, 3,3-dimethylbutoxymethyl,2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl,1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl and2,3-dimethylbutoxymethyl groups, and it is preferably a “C1-C3alkoxymethyl group”, and more preferably a methoxymethyl group, in R¹and R².

Oligosaccharide derivatives having the general formulas (I), (Ia) and(Ib) of the present invention can be converted to an acid addition saltin the case of having a basic group in accordance with ordinary methods.Examples of such salts include salts of halogenated hydroacids such ashydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodicacid; inorganic acid salts such as nitrates, perchlorates, sulfates andphosphates; salts of lower alkanesulfonic acids such as methanesulfonicacid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts ofarylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonicacid; salts of amino acids such as glutamic acid and aspartic acid; and,salts of carboxylic acids such as acetic acid, fumaric acid, tartaricacid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid,mandelic acid, ascorbic acid, lactic acid, gluconic acid and citricacid. The aforementioned salt is preferably a salt of a halogenatedhydroacid, and most preferably a hydrochloride.

Moreover, oligosaccharide derivatives having the aforementioned generalformulas (I), (Ia) and (Ib) can be converted to a metal salt inaccordance with ordinary methods since they have a hydroxyl group.Examples of such salts include salts of alkali metals such as lithium,sodium and potassium; salts of alkaline earth metals such as calcium,barium and magnesium; and, aluminium salts. The aforementioned metalsalt is preferably an alkali metal salt.

Oligosaccharide derivatives having the aforementioned general formulas(I), (Ia) and (Ib) of the present invention can be converted topharmacologically acceptable esters in accordance with ordinary methods.There are no particular limitations on such esters provided they can beused medically and their pharmacological acceptability is comparable tothat of the oligosaccharide derivatives of the aforementioned generalformulas (I), (Ia) and (Ib).

Examples of ester residues of oligosaccharide derivatives having theaforementioned general formulas (I), (Ia) and (Ib) of the presentinvention include C1-C6 alkyl groups (wherein said alkyl groups may besubstituted with a trialkylsilyl group), C7-C16 aralkyl groups, C1-C5alkyl groups substituted with C1-C6 alkanoyloxy groups, C1-C5 alkylgroups substituted with C1-C6 alkyloxycarbonyloxy groups, C1-C5 alkylgroups substituted with C5-C7 cycloalkyloxycarbonyloxy groups, C1-C5alkyl groups substituted with C6-C10 aryloxycarbonyloxy groups, and2-oxy-1,3-dioxolen-4-yl groups having a C1-C6 alkyl group as asubstituent at the 5-position.

Here, C1-C6 alkyl groups are preferably linear or branched alkyl groupshaving 1 to 4 carbon atoms, and more preferably are methyl, ethyl,propyl, isopropyl, butyl or isobutyl groups, and most preferably aremethyl groups or ethyl groups.

C1-C5 alkyl groups refer to linear or branched alkyl groups having 1 to5 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl orisobutyl groups, and most preferably methyl or ethyl groups.

C5-C7 cycloalkyl groups refer to 5- to 7-member saturated cyclichydrocarbon groups, examples of which include cyclopentyl, cyclohexyland cyclobutyl groups, and preferably cyclohexyl groups.

C6-C10 aryl groups refer to aromatic hydrocarbon groups having 6 to 10carbon atoms, examples of which include phenyl, indenyl and naphthylgroups, and preferably phenyl groups.

C7-C16 aralkyl groups refer to groups in which the aforementioned“C6-C10 aryl group” is bonded to the aforementioned “C1-C6 alkyl group”,examples of which include benzyl, α-naphtylmethyl, β-naphthylmethyl,indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl,triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl,2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl,2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl,2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl,2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl,1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl,5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl,4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl,2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, and6-naphthylhexyl groups. They are preferably “aralkyl groups” in whichthe number of carbons of the “alkyl group” is 1 to 4, and morepreferably benzyl groups in R¹ and R².

Specific preferable examples of ester residues include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl,1-(acetoxy)ethyl, propionyloxymethyl, 1-(propionyloxy)ethyl,butyryloxymethyl, 1-(butyryloxy)ethyl, isobutyryloxymethyl,1-(isobutyryloxy)ethyl, valeryloxymethyl, 1-(valeryloxy)ethyl,isovaleryloxymethyl, 1-(isovaleryloxy)ethyl, pivaloyloxymethyl,1-(pivaloyloxy)ethyl, methoxycarbonyloxymethyl,1-(methoxycarbonyloxy)ethyl, ethoxycarbonyloxymethyl,1-(ethoxycarbonyloxy)ethyl, propoxycarbonyloxymethyl,1-(propoxycarbonyloxy)ethyl, isopropoxycarbonyloxymethyl,1-(isopropoxycarbonyloxy)ethyl, butoxycarbonyloxymethyl,1-(butoxycarbonyloxy)ethyl, isobutoxycarbonyloxymethyl,1-(isobutoxycarbonyloxy)ethyl, t-butoxycarbonyloxymethyl,1-(t-butoxycarbonyloxy)ethyl, cyclopentanecarbonyloxymethyl,1-(cyclopentanecarbonyloxy)ethyl, cyclohexanecarbonyloxymethyl,1-(cyclohexanecarbonyloxy)ethyl, cyclopentyloxycarbonyloxymethyl,1-(cyclopentyloxycarbonyloxy)ethyl, cyclohexyloxycarbonyloxymethyl,1-(cyclohexyloxycarbonyloxy)ethyl, benzoyloxymethyl,1-(benzoyloxy)ethyl, phenoxycarbonyloxymethyl,1-(phenoxycarbonyloxy)ethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl or2-trimethylsilylethyl group.

Furthermore, oligosaccharide derivatives having the aforementionedgeneral formulas (I), (Ia) and (Ib) have various isomers. For example,optical isomers can be present in portion A and the bonding portion ofthe sugar in oligosaccharide derivatives having the aforementionedgeneral formulas (I), (Ia) and (Ib). In the aforementioned generalformulas (I), (Ia) and (Ib), these stereoisomers based on asymmetriccarbons and the racemic and non-racemic mixtures of these isomers areall indicated with a single formula. Thus, the present inventionincludes these isomers and mixtures of these isomers in variousproportions.

Moreover, in the case oligosaccharide derivatives having theaforementioned general formulas (I), (Ia) and (Ib), their salts or theiresters form solvates (for example, hydrates), the present inventionincludes these as well.

Moreover, compounds converted to oligosaccharide derivatives having theaforementioned general formulas (I), (Ia) and (Ib) that are metabolizedin the living body, their salts or their esters (for example, so-calledpro-drugs such as amide derivatives) are all included in the presentinvention.

In the present invention, (A1) is preferably the following generalformula (A1a) or (A1b):

and more preferably the following general formula (A1c):

(A2) is preferably the following general formula (A2a) or (A2b):

and more preferably the following general formula (A2c):

(A3) is preferably the following general formula (A3a):

R¹ is preferably a C1-C6 alkyl group or hydroxymethyl group, and morepreferably, a methyl group or hydroxymethyl group, and particularlypreferably a methyl group.

R² is preferably a C1-C6 alkyl group or hydroxymethyl group, morepreferably a methyl group or hydroxymethyl group, and particularlypreferably a hydroxymethyl group.

R³ is preferably a C1-C6 hydroxyalkyl group, hydroxyl group, halogenatom or hydrogen atom in general formulas (A1), (A1c) and (A1a), morepreferably a C1-C3 hydroxyalkyl group or hydrogen atom, and particularlypreferably a hydrogen atom. In general formulas (A2), (A2a), (A2b) and(A2c), R³ is preferably a C1-C6 hydroxyalkyl group, hydroxyl group,hydrogen atom or halogen atom, more preferably a C1-C3 hydroxyalkylgroup or hydrogen atom, and particularly preferably a hydroxymethylgroup. In general formulas (A3) and (A3a), R³ is preferably a C1-C6hydroxyalkyl group, amino group, hydroxyl group, hydrogen atom orhalogen atom, more preferably a hydroxymethyl group, hydroxyl group oramino group, and particularly preferably a hydroxyl group.

R⁴ is preferably a C1-C6 hydroxyalkyl group, hydrogen atom, hydroxylgroup or halogen atom in general formulas (A1), (A1c) and (A1a), morepreferably a hydroxyl group or halogen atom, particularly preferably ahydroxyl group or fluorine atom, and most preferably a hydroxyl group.In general formulas (A2), (A2a), (A2b) and (A2c), R⁴ is preferably aC1-C6 hydroxylalkyl group, hydrogen atom, halogen atom or hydroxylgroup, and more preferably a hydroxyl group. In general formulas (A3)and (A3a), R⁴ is preferably a C1-C6 hydroxyalkyl group, amino group,hydroxyl group, halogen atom or hydrogen atom, more preferably ahydroxyl group, halogen atom or hydrogen atom, and particularlypreferably a hydroxyl group.

R⁵ is preferably a hydroxyl group, halogen atom, C1-C6 hydroxyalkylgroup, C1-C6 haloalkyl group or hydrogen atom in general formulas (A1),(A1c) and (A1a), more preferably a C1-C6 hydroxyalkyl group,particularly preferably a C1-C3 hydroxyalkyl group, and most preferablya hydroxymethyl group. In general formulas (A3) and (A3a), R⁵ ispreferably a C1-C6 hydroxyalkyl group, hydroxyl group, hydrogen atom,halogen atom or amino group (and said amino group may be substitutedwith one or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl groups), morepreferably an amino group (and said amino group may be substituted withone or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl groups), andparticularly preferably an amino group.

R⁶ is preferably a C1-C6 hydroxyalkyl group, amino group, hydroxylgroup, hydrogen atom or halogen atom in general formulas (A3) and (A3a),more preferably a C1-C6 hydroxyalkyl group, particularly preferably aC1-C3 hydroxyalkyl group, and most preferably a hydroxymethyl group.

R⁷ is preferably a hydrogen atom, C1-C6 hydroxyalkyl group or C1-C6alkyl group, more preferably a hydrogen atom or methyl group, andparticularly preferably a hydrogen atom.

R⁸ and R⁹ are preferably C1-C3 hydroxyalkyl groups, halogen atoms,hydrogen atoms or hydroxyl groups, and more preferably hydrogen atoms orhydroxyl groups.

R¹⁰ is preferably a C1-C6 hydroxyalkyl group, more preferably a C1-C3hydroxyalkyl group, and particularly preferably a hydroxymethyl group.

R¹¹ is preferably a hydroxyl group.

n is preferably 1.

General formula (I) is preferably the following general formula (IA) or(IB):

A is preferably the following general formula (A1) or (A2):

and preferably (A1).

Specific examples of oligosaccharide derivatives having theaforementioned general formulas (I), (Ia) and (Ib) of the presentinvention, their pharmacologically acceptable salts and theirpharmacologically acceptable esters include the compounds listed tofollow. However, the present invention is not limited to theseexemplification compounds.

Furthermore, in the following Tables 1 to 5, “^(n)Pr” indicates ann-propyl group, “^(i)Pr” an i-propyl group, “^(n)Bu” an n-butyl group,“^(t)Bu” a t-butyl group, “^(i)Bu” an i-butyl group, “^(n)Pn” ann-pentyl group, and “^(n)Hex” an n-hexyl group.

TABLE 1 (Ia)

No. R¹ R² R⁷ R³ R⁴ R⁵ n 1-1  CH₃ CH₂OH H CH₂OH OH H 1 1-2  CH₃ CH₃ HCH₂OH OH H 1 1-3  CH₃ CH₂F H CH₂OH OH H 1 1-4  CH₃ CH₂OCH₃ H CH₂OH OH H1 1-5  CH₃ CH₂CH₃ H CH₂OH OH H 1 1-6  CH₃ ^(n)Pr H CH₂OH OH H 1 1-7  CH₃^(i)Pr H CH₂OH OH H 1 1-8  CH₃ ^(n)Bu H CH₂OH OH H 1 1-9  CH₃ ^(i)Bu HCH₂OH OH H 1 1-10  CH₃ ^(t)Bu H CH₂OH OH H 1 1-11  CH₃ ^(n)Pn H CH₂OH OHH 1 1-12  CH₃ ^(n)Hex H CH₂OH OH H 1 1-13  CH₃ CH₂OCH₂CH₃ H CH₂OH OH H 11-14  CH₃ CH₂O^(i)Pr H CH₂OH OH H 1 1-15  CH₃ CH₂O^(t)Bu H CH₂OH OH H 11-16  CH₃ (CH₂)₂F H CH₂OH OH H 1 1-17  CH₃ (CH₂)₃F H CH₂OH OH H 1 1-18 CH₃ (CH₂)₄F H CH₂OH OH H 1 1-19  CH₃ (CH₂)₅F H CH₂OH OH H 1 1-20  CH₃(CH₂)₆F H CH₂OH OH H 1 1-21  CH₃ CH₂Br H CH₂OH OH H 1 1-22  CH₃ CH₂Cl HCH₂OH OH H 1 1-23  CH₃ CH₂I H CH₂OH OH H 1 1-24  CH₃ CH₂OH CH₂CH₃ CH₂OHOH H 1 1-25  CH₃ CH₂OH ^(n)Pr CH₂OH OH H 1 1-26  CH₃ CH₂OH ^(i)Pr CH₂OHOH H 1 1-27  CH₃ CH₂OH ^(n)Bu CH₂OH OH H 1 1-28  CH₃ CH₂OH ^(t)Bu CH₂OHOH H 1 1-29  CH₃ CH₂OH ^(i)Bu CH₂OH OH H 1 1-30  CH₃ CH₂OH ^(n)Pn CH₂OHOH H 1 1-31  CH₃ CH₂OH ^(n)Hex CH₂OH OH H 1 1-32  CH₃ CH₂OH CH₂OH CH₂OHOH H 1 1-33  CH₃ CH₂OH (CH₂)₂OH CH₂OH OH H 1 1-34  CH₃ CH₂OH (CH₂)₃OHCH₂OH OH H 1 1-35  CH₃ CH₂OH (CH₂)₄OH CH₂OH OH H 1 1-36  CH₃ CH₂OH(CH₂)₅OH CH₂OH OH H 1 1-37  CH₃ CH₂OH (CH₂)₆OH CH₂OH OH H 1 1-38  CH₃CH₂OH CH₂F CH₂OH OH H 1 1-39  CH₃ CH₂OH CH₂Cl CH₂OH OH H 1 1-40  CH₃CH₂OH CH₂Br CH₂OH OH H 1 1-41  CH₃ CH₂OH CH₂I CH₂OH OH H 1 1-42  CH₃CH₂OH OH CH₂OH OH H 1 1-43  CH₃ CH₂OH OCH₃ CH₂OH OH H 1 1-44  CH₃ CH₂OHOCH₂CH₃ CH₂OH OH H 1 1-45  CH₃ CH₂OH O^(n)Pr CH₂OH OH H 1 1-46  CH₃CH₂OH O^(i)Pr CH₂OH OH H 1 1-47  CH₃ CH₂OH O^(n)Bu CH₂OH OH H 1 1-48 CH₃ CH₂OH O^(t)Bu CH₂OH OH H 1 1-49  CH₃ CH₂OH O^(i)Bu CH₂OH OH H 11-50  CH₃ CH₂OH O^(n)Pn CH₂OH OH H 1 1-51  CH₃ CH₂OH O^(n)Hex CH₂OH OH H1 1-52  CH₃ CH₂OH H CH₃ OH H 1 1-53  CH₃ CH₂OH H CH₂CH₃ OH H 1 1-54  CH₃CH₂OH H ^(n)Pr OH H 1 1-55  CH₃ CH₂OH H ^(i)Pr OH H 1 1-56  CH₃ CH₂OH H^(n)Bu OH H 1 1-57  CH₃ CH₂OH H ^(t)Bu OH H 1 1-58  CH₃ CH₂OH H ^(i)BuOH H 1 1-59  CH₃ CH₂OH H ^(n)Pn OH H 1 1-60  CH₃ CH₂OH H ^(n)Hex OH H 11-61  CH₃ CH₂OH H CH₂Br OH H 1 1-62  CH₃ CH₂OH H CH₂Cl OH H 1 1-63  CH₃CH₂OH H CH₂I OH H 1 1-64  CH₃ CH₂OH H NH₂ OH H 1 1-65  CH₃ CH₂OH HN(CH₃)₂ OH H 1 1-66  CH₃ CH₂OH H NHCH(CH₂OH)₂ OH H 1 1-67  CH₃ CH₂OH HOH OH H 1 1-68  CH₃ CH₂OH H H OH H 1 1-69  CH₃ CH₂OH H F OH H 1 1-70 CH₃ CH₂OH H Br OH H 1 1-71  CH₃ CH₂OH H Cl OH H 1 1-72  CH₃ CH₂OH H I OHH 1 1-73  CH₃ CH₂OH H CH₂OH CH₃ H 1 1-74  CH₃ CH₂OH H CH₂OH CH₂CH₃ H 11-75  CH₃ CH₂OH H CH₂OH CH₂OH H 1 1-76  CH₃ CH₂OH H CH₂OH (CH₂)₂OH H 11-77  CH₃ CH₂OH H CH₂OH (CH₂)₃OH H 1 1-78  CH₃ CH₂OH H CH₂OH (CH₂)₄OH H1 1-79  CH₃ CH₂OH H CH₂OH (CH₂)₅OH H 1 1-80  CH₃ CH₂OH H CH₂OH (CH₂)₆OHH 1 1-81  CH₃ CH₂OH H CH₂OH CH₂F H 1 1-82  CH₃ CH₂OH H CH₂OH CH₂Cl H 11-83  CH₃ CH₂OH H CH₂OH CH₂Br H 1 1-84  CH₃ CH₂OH H CH₂OH CH₂I H 1 1-85 CH₃ CH₂OH H CH₂OH H H 1 1-86  CH₃ CH₂OH H CH₂OH OCH₃ H 1 1-87  CH₃ CH₂OHH CH₂OH OCH₂CH₃ H 1 1-88  CH₃ CH₂OH H CH₂OH O^(n)Pr H 1 1-89  CH₃ CH₂OHH CH₂OH O^(i)Pr H 1 1-90  CH₃ CH₂OH H CH₂OH O^(n)Bu H 1 1-91  CH₃ CH₂OHH CH₂OH O^(i)Bu H 1 1-92  CH₃ CH₂OH H CH₂OH O^(t)Bu H 1 1-93  CH₃ CH₂OHH CH₂OH O^(n)Pn H 1 1-94  CH₃ CH₂OH H CH₂OH O^(n)Hex H 1 1-95  CH₃ CH₂OHH CH₂OH Br H 1 1-96  CH₃ CH₂OH H CH₂OH Cl H 1 1-97  CH₃ CH₂OH H CH₂OH IH 1 1-98  CH₃ CH₂OH H CH₂OH OH CH₃ 1 1-99  CH₃ CH₂OH H CH₂OH OH CH₂CH₃ 11-100 CH₃ CH₂OH H CH₂OH OH CH₂F 1 1-101 CH₃ CH₂OH H CH₂OH OH OCH₃ 11-102 CH₃ CH₂OH H CH₂OH OH OCH₂CH₃ 1 1-103 CH₃ CH₂OH H CH₂OH OH O^(n)Pr1 1-104 CH₃ CH₂OH H CH₂OH OH O^(i)Pr 1 1-105 CH₃ CH₂OH H CH₂OH OHO^(n)Bu 1 1-106 CH₃ CH₂OH H CH₂OH OH O^(i)Bu 1 1-107 CH₃ CH₂OH H CH₂OHOH O^(t)Bu 1 1-108 CH₃ CH₂OH H CH₂OH OH O^(n)Pn 1 1-109 CH₃ CH₂OH HCH₂OH OH O^(n)Hex 1 1-110 CH₃ CH₂OH H CH₂OH OH F 1 1-111 CH₃ CH₂OH CH₃CH₂OH OH H 1 1-112 CH₃ CH₃ CH₃ CH₂OH OH H 1 1-113 CH₃ CH₂F CH₃ CH₂OH OHH 1 1-114 CH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 1-115 CH₃ CH₂OH H CH₂OH F H 11-116 CH₃ CH₃ H CH₂OH F H 1 1-117 CH₃ CH₂F H CH₂OH F H 1 1-118 CH₃CH₂OCH₃ H CH₂OH F H 1 1-119 CH₃ CH₂OH H CH₂F OH H 1 1-120 CH₃ CH₃ H CH₂FOH H 1 1-121 CH₃ CH₂F H CH₂F OH H 1 1-122 CH₃ CH₂OCH₃ H CH₂F OH H 11-123 CH₃ CH₂OH H CH₂F F H 1 1-124 CH₃ CH₃ H CH₂F F H 1 1-125 CH₃ CH₂F HCH₂F F H 1 1-126 CH₃ CH₂OCH₃ H CH₂F F H 1 1-127 CH₃ CH₂OH H CH₂OH OH OH1 1-128 CH₃ CH₃ H CH₂OH OH OH 1 1-129 CH₃ CH₂F H CH₂OH OH OH 1 1-130 CH₃CH₂OH CH₃ CH₂OH OH OH 1 1-131 CH₃ CH₃ CH₃ CH₂OH OH OH 1 1-132 CH₃ CH₂FCH₃ CH₂OH OH OH 1 1-133 CH₃ CH₂OCH₃ CH₃ CH₂OH OH OH 1 1-134 CH₃ CH₂OH HCH₂F OH OH 1 1-135 CH₃ CH₃ H CH₂F OH OH 1 1-136 CH₃ CH₂F H CH₂F OH OH 11-137 CH₃ CH₂OCH₃ H CH₂F OH OH 1 1-138 CH₃ CH₂OH H CH₂OH F OH 1 1-139CH₃ CH₃ H CH₂OH F OH 1 1-140 CH₃ CH₂F H CH₂OH F OH 1 1-141 CH₃ CH₂OCH₃ HCH₂OH F OH 1 1-142 CH₃ CH₂OH H CH₂F F OH 1 1-143 CH₃ CH₃ H CH₂F F OH 11-144 CH₃ CH₂F H CH₂F F OH 1 1-145 CH₃ CH₂OCH₃ H CH₂F F OH 1 1-146 CH₃CH₂OCH₃ H CH₂OH OH OH 1 1-147 CH₂CH₃ CH₂OH H CH₂OH OH H 1 1-148 ^(n)PrCH₂OH H CH₂OH OH H 1 1-149 ^(i)Pr CH₂OH H CH₂OH OH H 1 1-150 ^(n)BuCH₂OH H CH₂OH OH H 1 1-151 ^(i)Bu CH₂OH H CH₂OH OH H 1 1-152 ^(t)BuCH₂OH H CH₂OH OH H 1 1-153 ^(n)Pn CH₂OH H CH₂OH OH H 1 1-154 ^(n)HexCH₂OH H CH₂OH OH H 1 1-155 CH₂OH CH₂OH H CH₂OH OH H 1 1-156 CH₂OH CH₃ HCH₂OH OH H 1 1-157 CH₂OH CH₂F H CH₂OH OH H 1 1-158 CH₂OH CH₂OCH₃ H CH₂OHOH H 1 1-159 CH₂OH CH₃ H CH₂OH OH H 1 1-160 CH₂OH CH₂F H CH₂OH OH H 11-161 CH₂OH CH₂OCH₃ H CH₂OH OH H 1 1-162 CH₂OH CH₂CH₃ H CH₂OH OH H 11-163 CH₂OH ^(n)Pr H CH₂OH OH H 1 1-164 CH₂OH ^(i)Pr H CH₂OH OH H 11-165 CH₂OH ^(n)Bu H CH₂OH OH H 1 1-166 CH₂OH ^(i)Bu H CH₂OH OH H 11-167 CH₂OH ^(t)Bu H CH₂OH OH H 1 1-168 CH₂OH ^(n)Pn H CH₂OH OH H 11-169 CH₂OH ^(n)Hex H CH₂OH OH H 1 1-170 CH₂OH CH₂OCH₂CH₃ H CH₂OH OH H 11-171 CH₂OH CH₂O^(i)Pr H CH₂OH OH H 1 1-172 CH₂OH CH₂O^(t)Bu H CH₂OH OHH 1 1-173 CH₂OH (CH₂)₂F H CH₂OH OH H 1 1-174 CH₂OH CH₂Br H CH₂OH OH H 11-175 CH₂OH CH₂Cl H CH₂OH OH H 1 1-176 CH₂OH CH₂I H CH₂OH OH H 1 1-177CH₂OH CH₂OH CH₂CH₃ CH₂OH OH H 1 1-178 CH₂OH CH₂OH ^(n)Pr CH₂OH OH H 11-179 CH₂OH CH₂OH ^(i)Pr CH₂OH OH H 1 1-180 CH₂OH CH₂OH ^(n)Bu CH₂OH OHH 1 1-181 CH₂OH CH₂OH ^(t)Bu CH₂OH OH H 1 1-182 CH₂OH CH₂OH ^(i)Bu CH₂OHOH H 1 1-183 CH₂OH CH₂OH ^(n)Pn CH₂OH OH H 1 1-184 CH₂OH CH₂OH ^(n)HexCH₂OH OH H 1 1-185 CH₂OH CH₂OH CH₂OH CH₂OH OH H 1 1-186 CH₂OH CH₂OH(CH₂)₂OH CH₂OH OH H 1 1-187 CH₂OH CH₂OH (CH₂)₃OH CH₂OH OH H 1 1-188CH₂OH CH₂OH (CH₂)₄OH CH₂OH OH H 1 1-189 CH₂OH CH₂OH (CH₂)₅OH CH₂OH OH H1 1-190 CH₂OH CH₂OH (CH₂)₆OH CH₂OH OH H 1 1-191 CH₂OH CH₂OH CH₂F CH₂OHOH H 1 1-192 CH₂OH CH₂OH CH₂Cl CH₂OH OH H 1 1-193 CH₂OH CH₂OH CH₂BrCH₂OH OH H 1 1-194 CH₂OH CH₂OH CH₂I CH₂OH OH H 1 1-195 CH₂OH CH₂OH OHCH₂OH OH H 1 1-196 CH₂OH CH₂OH OCH₃ CH₂OH OH H 1 1-197 CH₂OH CH₂OHOCH₂CH₃ CH₂OH OH H 1 1-198 CH₂OH CH₂OH O^(n)Pr CH₂OH OH H 1 1-199 CH₂OHCH₂OH O^(i)Pr CH₂OH OH H 1 1-200 CH₂OH CH₂OH O^(n)Bu CH₂OH OH H 1 1-201CH₂OH CH₂OH O^(t)Bu CH₂OH OH H 1 1-202 CH₂OH CH₂OH O^(i)Bu CH₂OH OH H 11-203 CH₂OH CH₂OH O^(n)Pn CH₂OH OH H 1 1-204 CH₂OH CH₂OH O^(n)Hex CH₂OHOH H 1 1-205 CH₂OH CH₂OH H CH₃ OH H 1 1-206 CH₂OH CH₂OH H CH₂CH₃ OH H 11-207 CH₂OH CH₂OH H CH₂Br OH H 1 1-208 CH₂OH CH₂OH H CH₂Cl OH H 1 1-209CH₂OH CH₂OH H CH₂I OH H 1 1-210 CH₂OH CH₂OH H OH OH H 1 1-211 CH₂OHCH₂OH H H OH H 1 1-212 CH₂OH CH₂OH H F OH H 1 1-213 CH₂OH CH₂OH H Br OHH 1 1-214 CH₂OH CH₂OH H Cl OH H 1 1-215 CH₂OH CH₂OH H I OH H 1 1-216CH₂OH CH₂OH H CH₂OH CH₃ H 1 1-217 CH₂OH CH₂OH H CH₂OH CH₂CH₃ H 1 1-218CH₂OH CH₂OH H CH₂OH ^(n)Pr H 1 1-219 CH₂OH CH₂OH H CH₂OH ^(i)Pr H 11-220 CH₂OH CH₂OH H CH₂OH ^(n)Bu H 1 1-221 CH₂OH CH₂OH H CH₂OH ^(i)Bu H1 1-222 CH₂OH CH₂OH H CH₂OH ^(t)Bu H 1 1-223 CH₂OH CH₂OH H CH₂OH ^(n)PnH 1 1-224 CH₂OH CH₂OH H CH₂OH ^(n)Hex H 1 1-225 CH₂OH CH₂OH H CH₂OHCH₂OH H 1 1-226 CH₂OH CH₂OH H CH₂OH CH₂F H 1 1-227 CH₂OH CH₂OH H CH₂OHCH₂Cl H 1 1-228 CH₂OH CH₂OH H CH₂OH CH₂Br H 1 1-229 CH₂OH CH₂OH H CH₂OHCH₂I H 1 1-230 CH₂OH CH₂OH H CH₂OH H H 1 1-231 CH₂OH CH₂OH H CH₂OH OCH₃H 1 1-232 CH₂OH CH₂OH H CH₂OH OCH₂CH₃ H 1 1-233 CH₂OH CH₂OH H CH₂OH Br H1 1-234 CH₂OH CH₂OH H CH₂OH Cl H 1 1-235 CH₂OH CH₂OH H CH₂OH I H 1 1-236CH₂OH CH₂OH H CH₂OH OH CH₃ 1 1-237 CH₂OH CH₂OH H CH₂OH OH CH₂CH₃ 1 1-238CH₂OH CH₂OH H CH₂OH OH CH₂F 1 1-239 CH₂OH CH₂OH H CH₂OH OH OCH₃ 1 1-240CH₂OH CH₂OH H CH₂OH OH OCH₂CH₃ 1 1-241 CH₂OH CH₂OH H CH₂OH OH F 1 1-242CH₂OH CH₂OH CH₃ CH₂OH OH H 1 1-243 CH₂OH CH₃ CH₃ CH₂OH OH H 1 1-244CH₂OH CH₂F CH₃ CH₂OH OH H 1 1-245 CH₂OH CH₂OCH₃ CH₃ CH₂OH OH H 1 1-246CH₂OH CH₂OH H CH₂F OH H 1 1-247 CH₂OH CH₃ H CH₂F OH H 1 1-248 CH₂OH CH₂FH CH₂F OH H 1 1-249 CH₂OH CH₂OH H CH₂OH F H 1 1-250 CH₂OH CH₃ H CH₂OH FH 1 1-251 CH₂OH CH₂F H CH₂OH F H 1 1-252 CH₂OH CH₂OCH₃ H CH₂OH F H 11-253 CH₂OH CH₂OCH₃ H CH₂F OH H 1 1-254 CH₂OH CH₂OH H CH₂F F H 1 1-255CH₂OH CH₃ H CH₂F F H 1 1-256 CH₂OH CH₂F H CH₂F F H 1 1-257 CH₂OH CH₂OCH₃H CH₂F F H 1 1-258 CH₂OH CH₂OH CH₃ CH₂OH OH OH 1 1-259 CH₂OH CH₂OH HCH₂OH OH OH 1 1-260 CH₂OH CH₃ H CH₂OH OH OH 1 1-261 CH₂OH CH₂F H CH₂OHOH OH 1 1-262 CH₂OH CH₂OCH₃ H CH₂OH OH OH 1 1-263 CH₂OH CH₃ CH₃ CH₂OH OHOH 1 1-264 CH₂OH CH₂F CH₃ CH₂OH OH OH 1 1-265 CH₂OH CH₂OCH₃ CH₃ CH₂OH OHOH 1 1-266 CH₂OH CH₂OH H CH₂F OH OH 1 1-267 CH₂OH CH₃ H CH₂F OH OH 11-268 CH₂OH CH₂F H CH₂F OH OH 1 1-269 CH₂OH CH₂OCH₃ H CH₂F OH OH 1 1-270CH₂OH CH₂OH H CH₂OH F OH 1 1-271 CH₂OH CH₃ H CH₂OH F OH 1 1-272 CH₂OHCH₂F H CH₂OH F OH 1 1-273 CH₂OH CH₂OCH₃ H CH₂OH F OH 1 1-274 CH₂OH CH₂OHH CH₂F F OH 1 1-275 CH₂OH CH₃ H CH₂F F OH 1 1-276 CH₂OH CH₂F H CH₂F F OH1 1-277 CH₂OH CH₂OCH₃ H CH₂F F OH 1 1-278 CH₂F CH₂OH H CH₂OH OH H 11-279 CH₂F CH₃ H CH₂OH OH H 1 1-280 CH₂F CH₂F H CH₂OH OH H 1 1-281 CH₂FCH₂OCH₃ H CH₂OH OH H 1 1-282 CH₂F CH₂CH₃ H CH₂OH OH H 1 1-283 CH₂FCH₂OCH₂CH₃ H CH₂OH OH H 1 1-284 CH₂F CH₂O^(i)Pr H CH₂OH OH H 1 1-285CH₂F CH₂O^(t)Bu H CH₂OH OH H 1 1-286 CH₂F CH₂OH H CH₃ OH H 1 1-287 CH₂FCH₂OH H CH₂CH₃ OH H 1 1-288 CH₂F CH₂OH H CH₂Br OH H 1 1-289 CH₂F CH₂OH HCH₂Cl OH H 1 1-290 CH₂F CH₂OH H CH₂I OH H 1 1-291 CH₂F CH₂OH H OH OH H 11-292 CH₂F CH₂OH H H OH H 1 1-293 CH₂F CH₂OH H F OH H 1 1-294 CH₂F CH₂OHH CH₂OH CH₃ H 1 1-295 CH₂F CH₂OH H CH₂OH CH₂CH₃ H 1 1-296 CH₂F CH₂OH HCH₂OH CH₂OH H 1 1-297 CH₂F CH₂OH H CH₂OH CH₂F H 1 1-298 CH₂F CH₂OH HCH₂OH H H 1 1-299 CH₂F CH₂OH H CH₂OH OCH₃ H 1 1-300 CH₂F CH₂OH H CH₂OHOCH₂CH₃ H 1 1-301 CH₂F CH₂OH H CH₂OH Br H 1 1-302 CH₂F CH₂OH H CH₂OH ClH 1 1-303 CH₂F CH₂OH H CH₂OH I H 1 1-304 CH₂F CH₂OH H CH₂OH OH CH₃ 11-305 CH₂F CH₂OH H CH₂OH OH CH₂CH₃ 1 1-306 CH₂F CH₂OH H CH₂OH OH CH₂F 11-307 CH₂F CH₂OH H CH₂OH OH OCH₃ 1 1-308 CH₂F CH₂OH H CH₂OH OH OCH₂CH₃ 11-309 CH₂F CH₂OH H CH₂OH OH F 1 1-310 CH₂F CH₂OH CH₃ CH₂OH OH H 1 1-311CH₂F CH₃ CH₃ CH₂OH OH H 1 1-312 CH₂F CH₂F CH₃ CH₂OH OH H 1 1-313 CH₂FCH₂OCH₃ CH₃ CH₂OH OH H 1 1-314 CH₂F CH₂OH H CH₂F OH H 1 1-315 CH₂F CH₃ HCH₂F OH H 1 1-316 CH₂F CH₂F H CH₂F OH H 1 1-317 CH₂F CH₂OH H CH₂OH F H 11-318 CH₂F CH₂OCH₃ H CH₂F OH H 1 1-319 CH₂F CH₃ H CH₂OH F H 1 1-320 CH₂FCH₂F H CH₂OH F H 1 1-321 CH₂F CH₂OCH₃ H CH₂OH F H 1 1-322 CH₂F CH₂OH HCH₂OH OH OH 1 1-323 CH₂F CH₃ H CH₂OH OH OH 1 1-324 CH₂F CH₂F H CH₂OH OHOH 1 1-325 CH₂F CH₂OCH₃ H CH₂OH OH OH 1 1-326 CH₂F CH₂OH CH₃ CH₂OH OH OH1 1-327 CH₂F CH₃ CH₃ CH₂OH OH OH 1 1-328 CH₂F CH₂F CH₃ CH₂OH OH OH 11-329 CH₂F CH₂OCH₃ CH₃ CH₂OH OH OH 1 1-330 CH₂F CH₂OH H CH₂F OH OH 11-331 CH₂F CH₃ H CH₂F OH OH 1 1-332 CH₂F CH₂F H CH₂F OH OH 1 1-333 CH₂FCH₂OCH₃ H CH₂F OH OH 1 1-334 CH₂F CH₂OH H CH₂F F H 1 1-335 CH₂F CH₃ HCH₂F F H 1 1-336 CH₂F CH₂F H CH₂F F H 1 1-337 CH₂F CH₂OCH₃ H CH₂F F H 11-338 CH₂F CH₂OH H CH₂F F OH 1 1-339 CH₂F CH₃ H CH₂F F OH 1 1-340 CH₂FCH₂F H CH₂F F OH 1 1-341 CH₂F CH₂OCH₃ H CH₂F F OH 1 1-342 CH₂F CH₂OH HCH₂OH F OH 1 1-343 CH₂F CH₃ H CH₂OH F OH 1 1-344 CH₂F CH₂F H CH₂OH F OH1 1-345 CH₂F CH₂OCH₃ H CH₂OH F OH 1 1-346 CH₂OCH₃ CH₂OH H CH₂F OH H 11-347 CH₂OCH₃ CH₃ H CH₂F OH H 1 1-348 CH₂OCH₃ CH₂F H CH₂F OH H 1 1-349CH₂OCH₃ CH₂OCH₃ H CH₂F OH H 1 1-350 CH₂OCH₃ CH₂OH H CH₂OH F H 1 1-351CH₂OCH₃ CH₃ H CH₂OH F H 1 1-352 CH₂OCH₃ CH₂F H CH₂OH F H 1 1-353 CH₂OCH₃CH₂OCH₃ H CH₂OH F H 1 1-354 CH₂OCH₃ CH₂OH H CH₂OH OH H 1 1-355 CH₂OCH₃CH₃ H CH₂OH OH H 1 1-356 CH₂OCH₃ CH₂F H CH₂OH OH H 1 1-357 CH₂OCH₃CH₂OCH₃ H CH₂OH OH H 1 1-358 CH₂OCH₃ CH₃ H CH₂OH OH H 1 1-359 CH₂OCH₃CH₂F H CH₂OH OH H 1 1-360 CH₂OCH₃ CH₂OCH₃ H CH₂OH OH H 1 1-361 CH₂OCH₃CH₂CH₃ H CH₂OH OH H 1 1-362 CH₂OCH₃ CH₂OCH₂CH₃ H CH₂OH OH H 1 1-363CH₂OCH₃ CH₂O^(i)Pr H CH₂OH OH H 1 1-364 CH₂OCH₃ CH₂O^(t)Bu H CH₂OH OH H1 1-365 CH₂OCH₃ CH₂OH H CH₃ OH H 1 1-366 CH₂OCH₃ CH₂OH H CH₂CH₃ OH H 11-367 CH₂OCH₃ CH₂OH H OH OH H 1 1-368 CH₂OCH₃ CH₂OH H H OH H 1 1-369CH₂OCH₃ CH₂OH H F OH H 1 1-370 CH₂OCH₃ CH₂OH H CH₂OH CH₃ H 1 1-371CH₂OCH₃ CH₂OH H CH₂OH CH₂CH₃ H 1 1-372 CH₂OCH₃ CH₂OH H CH₂OH CH₂OH H 11-373 CH₂OCH₃ CH₂OH H CH₂OH CH₂F H 1 1-374 CH₂OCH₃ CH₂OH H CH₂OH H H 11-375 CH₂OCH₃ CH₂OH H CH₂OH OCH₃ H 1 1-376 CH₂OCH₃ CH₂OH H CH₂OH OCH₂CH₃H 1 1-377 CH₂OCH₃ CH₂OH H CH₂OH Br H 1 1-378 CH₂OCH₃ CH₂OH H CH₂OH Cl H1 1-379 CH₂OCH₃ CH₂OH H CH₂OH I H 1 1-380 CH₂OCH₃ CH₂OH H CH₂OH OH CH₃ 11-381 CH₂OCH₃ CH₂OH H CH₂OH OH CH₂CH₃ 1 1-382 CH₂OCH₃ CH₂OH H CH₂OH OHCH₂F 1 1-383 CH₂OCH₃ CH₂OH H CH₂OH OH OCH₃ 1 1-384 CH₂OCH₃ CH₂OH H CH₂OHOH OCH₂CH₃ 1 1-385 CH₂OCH₃ CH₂OH H CH₂OH OH F 1 1-386 CH₂OCH₃ CH₂OH CH₃CH₂OH OH H 1 1-387 CH₂OCH₃ CH₃ CH₃ CH₂OH OH H 1 1-388 CH₂OCH₃ CH₂F CH₃CH₂OH OH H 1 1-389 CH₂OCH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 1-390 CH₂OCH₃ CH₂OHH CH₂F F H 1 1-391 CH₂OCH₃ CH₃ H CH₂F F H 1 1-392 CH₂OCH₃ CH₂F H CH₂F FH 1 1-393 CH₂OCH₃ CH₂OCH₃ H CH₂F F H 1 1-394 CH₂OCH₃ CH₂OH CH₃ CH₂OH OHOH 1 1-395 CH₂OCH₃ CH₃ CH₃ CH₂OH OH OH 1 1-396 CH₂OCH₃ CH₂F CH₃ CH₂OH OHOH 1 1-397 CH₂OCH₃ CH₃OCH₃ CH₃ CH₃OH OH OH 1 1-398 CH₂OCH₃ CH₂OH H CH₂FOH OH 1 1-399 CH₂OCH₃ CH₃ H CH₂F OH OH 1 1-400 CH₂OCH₃ CH₂F H CH₂F OH OH1 1-401 CH₂OCH₃ CH₂OCH₃ H CH₂F OH OH 1 1-402 CH₂OCH₃ CH₂OH H CH₂OH F OH1 1-403 CH₂OCH₃ CH₃ H CH₂OH F OH 1 1-404 CH₂OCH₃ CH₂F H CH₂OH F OH 11-405 CH₂OCH₃ CH₂OCH₃ H CH₂OH F OH 1 1-406 CH₂OCH₃ CH₂OH H CH₂F F OH 11-407 CH₂OCH₃ CH₃ H CH₂F F OH 1 1-408 CH₂OCH₃ CH₂F H CH₂F F OH 1 1-409CH₂OCH₃ CH₂OCH₃ H CH₂F F OH 1 1-410 CH₂OCH₂CH₃ CH₂OH H CH₂OH OH H 11-411 CH₂OCH₂CH₃ CH₃ H CH₂OH OH H 1 1-412 CH₂OCH₂CH₃ CH₂F H CH₂OH OH H 11-413 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH OH H 1 1-414 CH₂OCH₂CH₃ CH₂OH CH₃ CH₂OHOH H 1 1-415 CH₂OCH₂CH₃ CH₃ CH₃ CH₂OH OH H 1 1-416 CH₂OCH₂CH₃ CH₂F CH₃CH₂OH OH H 1 1-417 CH₂OCH₂CH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 1-418 CH₂OCH₂CH₃CH₂OH H CH₂F OH H 1 1-419 CH₂OCH₂CH₃ CH₃ H CH₂F OH H 1 1-420 CH₂OCH₂CH₃CH₂F H CH₂F OH H 1 1-421 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F OH H 1 1-422CH₂OCH₂CH₃ CH₂OH H CH₂OH F H 1 1-423 CH₂OCH₂CH₃ CH₃ H CH₂OH F H 1 1-424CH₂OCH₂CH₃ CH₂F H CH₂OH F H 1 1-425 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH F H 11-426 CH₂OCH₂CH₃ CH₂OH H CH₂F F H 1 1-427 CH₂OCH₂CH₃ CH₃ H CH₂F F H 11-428 CH₂OCH₂CH₃ CH₂F H CH₂F F H 1 1-429 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F F H 11-430 CH₂OCH₂CH₃ CH₂OH H CH₂OH OH OH 1 1-431 CH₂OCH₂CH₃ CH₃ H CH₂OH OHOH 1 1-432 CH₂OCH₂CH₃ CH₂F H CH₂OH OH OH 1 1-433 CH₂OCH₂CH₃ CH₂OCH₃ HCH₂OH OH OH 1 1-434 CH₂OCH₂CH₃ CH₂OH CH₃ CH₂OH OH OH 1 1-435 CH₂OCH₂CH₃CH₃ CH₃ CH₂OH OH OH 1 1-436 CH₂OCH₂CH₃ CH₂F CH₃ CH₂OH OH OH 1 1-437CH₂OCH₂CH₃ CH₂OCH₃ CH₃ CH₂OH OH OH 1 1-438 CH₂OCH₂CH₃ CH₂OH H CH₂F OH OH1 1-439 CH₂OCH₂CH₃ CH₃ H CH₂F OH OH 1 1-440 CH₂OCH₂CH₃ CH₂F H CH₂F OH OH1 1-441 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F OH OH 1 1-442 CH₂OCH₂CH₃ CH₂OH H CH₂OHF OH 1 1-443 CH₂OCH₂CH₃ CH₃ H CH₂OH F OH 1 1-444 CH₂OCH₂CH₃ CH₂F H CH₂OHF OH 1 1-445 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH F OH 1 1-446 CH₂OCH₂CH₃ CH₂OH HCH₂F F OH 1 1-447 CH₂OCH₂CH₃ CH₃ H CH₂F F OH 1 1-448 CH₂OCH₂CH₃ CH₂F HCH₂F F OH 1 1-449 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F F OH 1 1-450 CH₂O^(n)PrCH₂OH H CH₂OH OH H 1 1-451 CH₂O^(i)Pr CH₂OH H CH₂OH OH H 1 1-452CH₂O^(n)Bu CH₂OH H CH₂OH OH H 1 1-453 CH₂O^(i)Bu CH₂OH H CH₂OH OH H 11-454 CH₂O^(t)Bu CH₂OH H CH₂OH OH H 1 1-455 CH₂O^(n)Pn CH₂OH H CH₂OH OHH 1 1-456 CH₂O^(n)Hex CH₂OH H CH₂OH OH H 1 1-457 CH₂Cl CH₂OH H CH₂OH OHH 1 1-458 CH₂Cl CH₃ H CH₂OH OH H 1 1-459 CH₂Cl CH₂F H CH₂OH OH H 1 1-460CH₂Cl CH₂OCH₃ H CH₂OH OH H 1 1-461 CH₂Cl CH₂OH CH₃ CH₂OH OH H 1 1-462CH₂Cl CH₃ CH₃ CH₂OH OH H 1 1-463 CH₂Cl CH₂F CH₃ CH₂OH OH H 1 1-464 CH₂ClCH₂OCH₃ CH₃ CH₂OH OH H 1 1-465 CH₂Cl CH₃OH H CH₂F OH H 1 1-466 CH₂Cl CH₃H CH₂F OH H 1 1-467 CH₂Cl CH₂F H CH₂F OH H 1 1-468 CH₂Cl CH₂OCH₃ H CH₂FOH H 1 1-469 CH₂Cl CH₂OH H CH₂OH F H 1 1-470 CH₂Cl CH₃ H CH₂OH F H 11-471 CH₂Cl CH₂F H CH₂OH F H 1 1-472 CH₂Cl CH₂OCH₃ H CH₂OH F H 1 1-473CH₂Cl CH₂OH H CH₂F F H 1 1-474 CH₂Cl CH₃ H CH₂F F H 1 1-475 CH₂Cl CH₂F HCH₂F F H 1 1-476 CH₂Cl CH₂OCH₃ H CH₂F F H 1 1-477 CH₂Cl CH₂OH H CH₂OH OHOH 1 1-478 CH₂Cl CH₃ H CH₂OH OH OH 1 1-479 CH₂Cl CH₂F H CH₂OH OH OH 11-480 CH₂Cl CH₂OCH₃ H CH₂OH OH OH 1 1-481 CH₂Cl CH₂OH H CH₂F OH OH 11-482 CH₂Cl CH₃ H CH₂F OH OH 1 1-483 CH₂Cl CH₂F H CH₂F OH OH 1 1-484CH₂Cl CH₂OCH₃ H CH₂F OH OH 1 1-485 CH₂Cl CH₂OH H CH₂OH F OH 1 1-486CH₂Cl CH₃ H CH₂OH F OH 1 1-487 CH₂Cl CH₂F H CH₂OH F OH 1 1-488 CH₂ClCH₂OCH₃ H CH₂OH F OH 1 1-489 CH₂Cl CH₂OH H CH₂F F OH 1 1-490 CH₂Cl CH₃ HCH₂F F OH 1 1-491 CH₂Cl CH₂F H CH₂F F OH 1 1-492 CH₂Cl CH₂OCH₃ H CH₂F FOH 1 1-493 CH₂Cl CH₂OH CH₃ CH₂OH OH OH 1 1-494 CH₂Cl CH₃ CH₃ CH₂OH OH OH1 1-495 CH₂Cl CH₂F CH₃ CH₂OH OH OH 1 1-496 CH₂Cl CH₂OCH₃ CH₃ CH₂OH OH OH1 1-497 CH₂Br CH₂OH H CH₂OH OH H 1 1-498 CH₂Br CH₃ H CH₂OH OH H 1 1-499CH₂Br CH₂F H CH₂OH OH H 1 1-500 CH₂Br CH₂OCH₃ H CH₂OH OH H 1 1-501 CH₂BrCH₂OH CH₃ CH₂OH OH H 1 1-502 CH₂Br CH₃ CH₃ CH₂OH OH H 1 1-503 CH₂Br CH₂FCH₃ CH₂OH OH H 1 1-504 CH₂Br CH₂OCH₃ CH₃ CH₂OH OH H 1 1-505 CH₂Br CH₂OHH CH₂F OH H 1 1-506 CH₂Br CH₃ H CH₂F OH H 1 1-507 CH₂Br CH₂F H CH₂F OH H1 1-508 CH₂Br CH₂OCH₃ H CH₂F OH H 1 1-509 CH₂Br CH₂OH H CH₂OH F H 11-510 CH₂Br CH₃ H CH₂OH F H 1 1-511 CH₂Br CH₂F H CH₂OH F H 1 1-512 CH₂BrCH₂OCH₃ H CH₂OH F H 1 1-513 CH₂Br CH₂OH H CH₂F F H 1 1-514 CH₂Br CH₃ HCH₂F F H 1 1-515 CH₂Br CH₂F H CH₂F F H 1 1-516 CH₂Br CH₂OCH₃ H CH₂F F H1 1-517 CH₂Br CH₂OH H CH₂OH OH OH 1 1-518 CH₂Br CH₃ H CH₂OH OH OH 11-519 CH₂Br CH₂F H CH₂OH OH OH 1 1-520 CH₂Br CH₂OH CH₃ CH₂OH OH OH 11-521 CH₂Br CH₃ CH₃ CH₂OH OH OH 1 1-522 CH₂Br CH₂F CH₃ CH₂OH OH OH 11-523 CH₂Br CH₂OCH₃ CH₃ CH₂OH OH OH 1 1-524 CH₂Br CH₂OH H CH₂F OH OH 11-525 CH₂Br CH₃ H CH₂F OH OH 1 1-526 CH₂Br CH₂F H CH₂F OH OH 1 1-527CH₂Br CH₂OCH₃ H CH₂F OH OH 1 1-528 CH₂Br CH₂OH H CH₂OH F OH 1 1-529CH₂Br CH₃ H CH₂OH F OH 1 1-530 CH₂Br CH₂F H CH₂OH F OH 1 1-531 CH₂BrCH₂OCH₃ H CH₂OH F OH 1 1-532 CH₂Br CH₂OH H CH₂F F OH 1 1-533 CH₂Br CH₃ HCH₂F F OH 1 1-534 CH₂Br CH₂F H CH₂F F OH 1 1-535 CH₂Br CH₂OCH₃ H CH₂F FOH 1 1-536 CH₂Br CH₂OCH₃ H CH₂OH OH OH 1 1-537 CH₂I CH₂OH H CH₂OH OH H 11-538 CH₃ CH₂OH H CH₂OH OH H 2 1-539 CH₃ CH₃ H CH₂OH OH H 2 1-540 CH₃CH₂F H CH₂OH OH H 2 1-541 CH₃ CH₂OH H CH₂OH F H 2 1-542 CH₃ CH₃ H CH₂OHF H 2 1-543 CH₃ CH₂F H CH₂OH F H 2 1-544 CH₃ CH₂OH H CH₂F OH H 2 1-545CH₃ CH₃ H CH₂F OH H 2 1-546 CH₃ CH₂F H CH₂F OH H 2 1-547 CH₂OH CH₂OH HCH₂OH OH H 2 1-548 CH₂OH CH₃ H CH₂OH OH H 2 1-549 CH₂OH CH₂F H CH₂OH OHH 2 1-550 CH₂F CH₂OH H CH₂OH OH H 2 1-551 CH₂F CH₃ H CH₂OH OH H 2 1-552CH₂F CH₂F H CH₂OH OH H 2 1-553 CH₂OCH₃ CH₂OH H CH₂OH OH H 2 1-554CH₂OCH₃ CH₃ H CH₂OH OH H 2 1-555 CH₂OCH₃ CH₂F H CH₂OH OH H 2 1-556 CH₃CH₂OH H H OH CH₂OH 1 1-557 CH₃ CH₂OH H CH₂OH OH CH₂OH 1 1-558 CH₂OHCH₂OH H CH₂OH OH CH₂OH 1

TABLE 2 (Ia′)

No. R¹ R² R⁷ R³ R⁴ R⁵ n 2-1  CH₃ CH₂OH H CH₂OH OH H 1 2-2  CH₃ CH₃ HCH₂OH OH H 1 2-3  CH₃ CH₂F H CH₂OH OH H 1 2-4  CH₃ CH₂OCH₃ H CH₂OH OH H1 2-5  CH₃ CH₂CH₃ H CH₂OH OH H 1 2-6  CH₃ ^(n)Pr H CH₂OH OH H 1 2-7  CH₃^(i)Pr H CH₂OH OH H 1 2-8  CH₃ ^(n)Bu H CH₂OH OH H 1 2-9  CH₃ ^(i)Bu HCH₂OH OH H 1 2-10  CH₃ ^(t)Bu H CH₂OH OH H 1 2-11  CH₃ ^(n)Pn H CH₂OH OHH 1 2-12  CH₃ ^(n)Hex H CH₂OH OH H 1 2-13  CH₃ CH₂OCH₂CH₃ H CH₂OH OH H 12-14  CH₃ CH₂O^(i)Pr H CH₂OH OH H 1 2-15  CH₃ CH₂O^(t)Bu H CH₂OH OH H 12-16  CH₃ (CH₂)₂F H CH₂OH OH H 1 2-17  CH₃ (CH₂)₃F H CH₂OH OH H 1 2-18 CH₃ (CH₂)₄F H CH₂OH OH H 1 2-19  CH₃ (CH₂)₅F H CH₂OH OH H 1 2-20  CH₃(CH₂)₆F H CH₂OH OH H 1 2-21  CH₃ CH₂Br H CH₂OH OH H 1 2-22  CH₃ CH₂Cl HCH₂OH OH H 1 2-23  CH₃ CH₂I H CH₂OH OH H 1 2-24  CH₃ CH₂OH CH₂CH₃ CH₂OHOH H 1 2-25  CH₃ CH₂OH ^(n)Pr CH₂OH OH H 1 2-26  CH₃ CH₂OH ^(i)Pr CH₂OHOH H 1 2-27  CH₃ CH₂OH ^(n)Bu CH₂OH OH H 1 2-28  CH₃ CH₂OH ^(t)Bu CH₂OHOH H 1 2-29  CH₃ CH₂OH ^(i)Bu CH₂OH OH H 1 2-30  CH₃ CH₂OH ^(n)Pn CH₂OHOH H 1 2-31  CH₃ CH₂OH ^(n)Hex CH₂OH OH H 1 2-32  CH₃ CH₂OH CH₂OH CH₂OHOH H 1 2-33  CH₃ CH₂OH (CH₂)₂OH CH₂OH OH H 1 2-34  CH₃ CH₂OH (CH₂)₃OHCH₂OH OH H 1 2-35  CH₃ CH₂OH (CH₂)₄OH CH₂OH OH H 1 2-36  CH₃ CH₂OH(CH₂)₅OH CH₂OH OH H 1 2-37  CH₃ CH₂OH (CH₂)₆OH CH₂OH OH H 1 2-38  CH₃CH₂OH CH₂F CH₂OH OH H 1 2-39  CH₃ CH₂OH CH₂Cl CH₂OH OH H 1 2-40  CH₃CH₂OH CH₂Br CH₂OH OH H 1 2-41  CH₃ CH₂OH CH₂I CH₂OH OH H 1 2-42  CH₃CH₂OH OH CH₂OH OH H 1 2-43  CH₃ CH₂OH OCH₃ CH₂OH OH H 1 2-44  CH₃ CH₂OHOCH₂CH₃ CH₂OH OH H 1 2-45  CH₃ CH₂OH O^(n)Pr CH₂OH OH H 1 2-46  CH₃CH₂OH O^(i)Pr CH₂OH OH H 1 2-47  CH₃ CH₂OH O^(n)Bu CH₂OH OH H 1 2-48 CH₃ CH₂OH O^(t)Bu CH₂OH OH H 1 2-49  CH₃ CH₂OH O^(i)Bu CH₂OH OH H 12-50  CH₃ CH₂OH O^(n)Pn CH₂OH OH H 1 2-51  CH₃ CH₂OH O^(n)Hex CH₂OH OH H1 2-52  CH₃ CH₂OH H CH₃ OH H 1 2-53  CH₃ CH₂OH H CH₂CH₃ OH H 1 2-54  CH₃CH₂OH H ^(n)Pr OH H 1 2-55  CH₃ CH₂OH H ^(i)Pr OH H 1 2-56  CH₃ CH₂OH H^(n)Bu OH H 1 2-57  CH₃ CH₂OH H ^(t)Bu OH H 1 2-58  CH₃ CH₂OH H ^(i)BuOH H 1 2-59  CH₃ CH₂OH H ^(n)Pn OH H 1 2-60  CH₃ CH₂OH H ^(n)Hex OH H 12-61  CH₃ CH₂OH H CH₂Br OH H 1 2-62  CH₃ CH₂OH H CH₂Cl OH H 1 2-63  CH₃CH₂OH H CH₂I OH H 1 2-64  CH₃ CH₂OH H NH₂ OH H 1 2-65  CH₃ CH₂OH HN(CH₃)₂ OH H 1 2-66  CH₃ CH₂OH H NHCH(CH₂OH)₂ OH H 1 2-67  CH₃ CH₂OH HOH OH H 1 2-68  CH₃ CH₂OH H H OH H 1 2-69  CH₃ CH₂OH H F OH H 1 2-70 CH₃ CH₂OH H Br OH H 1 2-71  CH₃ CH₂OH H Cl OH H 1 2-72  CH₃ CH₂OH H I OHH 1 2-73  CH₃ CH₂OH H CH₂OH CH₃ H 1 2-74  CH₃ CH₂OH H CH₂OH CH₂CH₃ H 12-75  CH₃ CH₂OH H CH₂OH CH₂OH H 1 2-76  CH₃ CH₂OH H CH₂OH (CH₂)₂OH H 12-77  CH₃ CH₂OH H CH₂OH (CH₂)₃OH H 1 2-78  CH₃ CH₂OH H CH₂OH (CH₂)₄OH H1 2-79  CH₃ CH₂OH H CH₂OH (CH₂)₅OH H 1 2-80  CH₃ CH₂OH H CH₂OH (CH₂)₆OHH 1 2-81  CH₃ CH₂OH H CH₂OH CH₂F H 1 2-82  CH₃ CH₂OH H CH₂OH CH₂Cl H 12-83  CH₃ CH₂OH H CH₂OH CH₂Br H 1 2-84  CH₃ CH₂OH H CH₂OH CH₂I H 1 2-85 CH₃ CH₂OH H CH₂OH H H 1 2-86  CH₃ CH₂OH H CH₂OH OCH₃ H 1 2-87  CH₃ CH₂OHH CH₂OH OCH₂CH₃ H 1 2-88  CH₃ CH₂OH H CH₂OH O^(n)Pr H 1 2-89  CH₃ CH₂OHH CH₂OH O^(i)Pr H 1 2-90  CH₃ CH₂OH H CH₂OH O^(n)Bu H 1 2-91  CH₃ CH₂OHH CH₂OH O^(i)Bu H 1 2-92  CH₃ CH₂OH H CH₂OH O^(t)Bu H 1 2-93  CH₃ CH₂OHH CH₂OH O^(n)Pn H 1 2-94  CH₃ CH₂OH H CH₂OH O^(n)Hex H 1 2-95  CH₃ CH₂OHH CH₂OH Br H 1 2-96  CH₃ CH₂OH H CH₂OH Cl H 1 2-97  CH₃ CH₂OH H CH₂OH IH 1 2-98  CH₃ CH₂OH H CH₂OH OH CH₃ 1 2-99  CH₃ CH₂OH H CH₂OH OH CH₂CH₃ 12-100 CH₃ CH₂OH H CH₂OH OH CH₂F 1 2-101 CH₃ CH₂OH H CH₂OH OH OCH₃ 12-102 CH₃ CH₂OH H CH₂OH OH OCH₂CH₃ 1 2-103 CH₃ CH₂OH H CH₂OH OH O^(n)Pr1 2-104 CH₃ CH₂OH H CH₂OH OH O^(i)Pr 1 2-105 CH₃ CH₂OH H CH₂OH OHO^(n)Bu 1 2-106 CH₃ CH₂OH H CH₂OH OH O^(i)Bu 1 2-107 CH₃ CH₂OH H CH₂OHOH O^(t)Bu 1 2-108 CH₃ CH₂OH H CH₂OH OH O^(n)Pn 1 2-109 CH₃ CH₂OH HCH₂OH OH O^(n)Hex 1 2-110 CH₃ CH₂OH H CH₂OH OH F 1 2-111 CH₃ CH₂OH CH₃CH₂OH OH H 1 2-112 CH₃ CH₃ CH₃ CH₂OH OH H 1 2-113 CH₃ CH₂F CH₃ CH₂OH OHH 1 2-114 CH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 2-115 CH₃ CH₂OH H CH₂OH F H 12-116 CH₃ CH₃ H CH₂OH F H 1 2-117 CH₃ CH₂F H CH₂OH F H 1 2-118 CH₃CH₂OCH₃ H CH₂OH F H 1 2-119 CH₃ CH₂OH H CH₂F OH H 1 2-120 CH₃ CH₃ H CH₂FOH H 1 2-121 CH₃ CH₂F H CH₂F OH H 1 2-122 CH₃ CH₂OCH₃ H CH₂F OH H 12-123 CH₃ CH₂OH H CH₂F F H 1 2-124 CH₃ CH₃ H CH₂F F H 1 2-125 CH₃ CH₂F HCH₂F F H 1 2-126 CH₃ CH₂OCH₃ H CH₂F F H 1 2-127 CH₃ CH₂OH H CH₂OH OH OH1 2-128 CH₃ CH₃ H CH₂OH OH OH 1 2-129 CH₃ CH₂F H CH₂OH OH OH 1 2-130 CH₃CH₂OH CH₃ CH₂OH OH OH 1 2-131 CH₃ CH₃ CH₃ CH₂OH OH OH 1 2-132 CH₃ CH₂FCH₃ CH₂OH OH OH 1 2-133 CH₃ CH₂OCH₃ CH₃ CH₂OH OH OH 1 2-134 CH₃ CH₂OH HCH₂F OH OH 1 2-135 CH₃ CH₃ H CH₂F OH OH 1 2-136 CH₃ CH₂F H CH₂F OH OH 12-137 CH₃ CH₂OCH₃ H CH₂F OH OH 1 2-138 CH₃ CH₂OH H CH₂OH F OH 1 2-139CH₃ CH₃ H CH₂OH F OH 1 2-140 CH₃ CH₂F H CH₂OH F OH 1 2-141 CH₃ CH₂OCH₃ HCH₂OH F OH 1 2-142 CH₃ CH₂OH H CH₂F F OH 1 2-143 CH₃ CH₃ H CH₂F F OH 12-144 CH₃ CH₂F H CH₂F F OH 1 2-145 CH₃ CH₂OCH₃ H CH₂F F OH 1 2-146 CH₃CH₂OCH₃ H CH₂OH OH OH 1 2-147 CH₂CH₃ CH₂OH H CH₂OH OH H 1 2-148 ^(n)PrCH₂OH H CH₂OH OH H 1 2-149 ^(i)Pr CH₂OH H CH₂OH OH H 1 2-150 ^(n)BuCH₂OH H CH₂OH OH H 1 2-151 ^(i)Bu CH₂OH H CH₂OH OH H 1 2-152 ^(t)BuCH₂OH H CH₂OH OH H 1 2-153 ^(n)Pn CH₂OH H CH₂OH OH H 1 2-154 ^(n)HexCH₂OH H CH₂OH OH H 1 2-155 CH₂OH CH₂OH H CH₂OH OH H 1 2-156 CH₂OH CH₃ HCH₂OH OH H 1 2-157 CH₂OH CH₂F H CH₂OH OH H 1 2-158 CH₂OH CH₂OCH₃ H CH₂OHOH H 1 2-159 CH₂OH CH₃ H CH₂OH OH H 1 2-160 CH₂OH CH₂F H CH₂OH OH H 12-161 CH₂OH CH₂OCH₃ H CH₂OH OH H 1 2-162 CH₂OH CH₂CH₃ H CH₂OH OH H 12-163 CH₂OH ^(n)Pr H CH₂OH OH H 1 2-164 CH₂OH ^(i)Pr H CH₂OH OH H 12-165 CH₂OH ^(n)Bu H CH₂OH OH H 1 2-166 CH₂OH ^(i)Bu H CH₂OH OH H 12-167 CH₂OH ^(t)Bu H CH₂OH OH H 1 2-168 CH₂OH ^(n)Pn H CH₂OH OH H 12-169 CH₂OH ^(n)Hex H CH₂OH OH H 1 2-170 CH₂OH CH₂OCH₂CH₃ H CH₂OH OH H 12-171 CH₂OH CH₂O^(i)Pr H CH₂OH OH H 1 2-172 CH₂OH CH₂O^(t)Bu H CH₂OH OHH 1 2-173 CH₂OH (CH₂)₂F H CH₂OH OH H 1 2-174 CH₂OH CH₂Br H CH₂OH OH H 12-175 CH₂OH CH₂Cl H CH₂OH OH H 1 2-176 CH₂OH CH₂I H CH₂OH OH H 1 2-177CH₂OH CH₂OH CH₂CH₃ CH₂OH OH H 1 2-178 CH₂OH CH₂OH ^(n)Pr CH₂OH OH H 12-179 CH₂OH CH₂OH ^(i)Pr CH₂OH OH H 1 2-180 CH₂OH CH₂OH ^(n)Bu CH₂OH OHH 1 2-181 CH₂OH CH₂OH ^(t)Bu CH₂OH OH H 1 2-182 CH₂OH CH₂OH ^(i)Bu CH₂OHOH H 1 2-183 CH₂OH CH₂OH ^(n)Pn CH₂OH OH H 1 2-184 CH₂OH CH₂OH ^(n)HexCH₂OH OH H 1 2-185 CH₂OH CH₂OH CH₂OH CH₂OH OH H 1 2-186 CH₂OH CH₂OH(CH₂)₂OH CH₂OH OH H 1 2-187 CH₂OH CH₂OH (CH₂)₃OH CH₂OH OH H 1 2-188CH₂OH CH₂OH (CH₂)₄OH CH₂OH OH H 1 2-189 CH₂OH CH₂OH (CH₂)₅OH CH₂OH OH H1 2-190 CH₂OH CH₂OH (CH₂)₆OH CH₂OH OH H 1 2-191 CH₂OH CH₂OH CH₂F CH₂OHOH H 1 2-192 CH₂OH CH₂OH CH₂Cl CH₂OH OH H 1 2-193 CH₂OH CH₂OH CH₂BrCH₂OH OH H 1 2-194 CH₂OH CH₂OH CH₂I CH₂OH OH H 1 2-195 CH₂OH CH₂OH OHCH₂OH OH H 1 2-196 CH₂OH CH₂OH OCH₃ CH₂OH OH H 1 2-197 CH₂OH CH₂OHOCH₂CH₃ CH₂OH OH H 1 2-198 CH₂OH CH₂OH O^(n)Pr CH₂OH OH H 1 2-199 CH₂OHCH₂OH O^(i)Pr CH₂OH OH H 1 2-200 CH₂OH CH₂OH O^(n)Bu CH₂OH OH H 1 2-201CH₂OH CH₂OH O^(t)Bu CH₂OH OH H 1 2-202 CH₂OH CH₂OH O^(i)Bu CH₂OH OH H 12-203 CH₂OH CH₂OH O^(n)Pn CH₂OH OH H 1 2-204 CH₂OH CH₂OH O^(n)Hex CH₂OHOH H 1 2-205 CH₂OH CH₂OH H CH₃ OH H 1 2-206 CH₂OH CH₂OH H CH₂CH₃ OH H 12-207 CH₂OH CH₂OH H CH₂Br OH H 1 2-208 CH₂OH CH₂OH H CH₂Cl OH H 1 2-209CH₂OH CH₂OH H CH₂I OH H 1 2-210 CH₂OH CH₂OH H OH OH H 1 2-211 CH₂OHCH₂OH H H OH H 1 2-212 CH₂OH CH₂OH H F OH H 1 2-213 CH₂OH CH₂OH H Br OHH 1 2-214 CH₂OH CH₂OH H Cl OH H 1 2-215 CH₂OH CH₂OH H I OH H 1 2-216CH₂OH CH₂OH H CH₂OH CH₃ H 1 2-217 CH₂OH CH₂OH H CH₂OH CH₂CH₃ H 1 2-218CH₂OH CH₂OH H CH₂OH ^(n)Pr H 1 2-219 CH₂OH CH₂OH H CH₂OH ^(i)Pr H 12-220 CH₂OH CH₂OH H CH₂OH ^(n)Bu H 1 2-221 CH₂OH CH₂OH H CH₂OH ^(i)Bu H1 2-222 CH₂OH CH₂OH H CH₂OH ^(t)Bu H 1 2-223 CH₂OH CH₂OH H CH₂OH ^(n)PnH 1 2-224 CH₂OH CH₂OH H CH₂OH ^(n)Hex H 1 2-225 CH₂OH CH₂OH H CH₂OHCH₂OH H 1 2-226 CH₂OH CH₂OH H CH₂OH CH₂F H 1 2-227 CH₂OH CH₂OH H CH₂OHCH₂Cl H 1 2-228 CH₂OH CH₂OH H CH₂OH CH₂Br H 1 2-229 CH₂OH CH₂OH H CH₂OHCH₂I H 1 2-230 CH₂OH CH₂OH H CH₂OH H H 1 2-231 CH₂OH CH₂OH H CH₂OH OCH₃H 1 2-232 CH₂OH CH₂OH H CH₂OH OCH₂CH₃ H 1 2-233 CH₂OH CH₂OH H CH₂OH Br H1 2-234 CH₂OH CH₂OH H CH₂OH Cl H 1 2-235 CH₂OH CH₂OH H CH₂OH I H 1 2-236CH₂OH CH₂OH H CH₂OH OH CH₃ 1 2-237 CH₂OH CH₂OH H CH₂OH OH CH₂CH₃ 1 2-238CH₂OH CH₂OH H CH₂OH OH CH₂F 1 2-239 CH₂OH CH₂OH H CH₂OH OH OCH₃ 1 2-240CH₂OH CH₂OH H CH₂OH OH OCH₂CH₃ 1 2-241 CH₂OH CH₂OH H CH₂OH OH F 1 2-242CH₂OH CH₂OH CH₃ CH₂OH OH H 1 2-243 CH₂OH CH₃ CH₃ CH₂OH OH H 1 2-244CH₂OH CH₂F CH₃ CH₂OH OH H 1 2-245 CH₂OH CH₂OCH₃ CH₃ CH₂OH OH H 1 2-246CH₂OH CH₂OH H CH₂F OH H 1 2-247 CH₂OH CH₃ H CH₂F OH H 1 2-248 CH₂OH CH₂FH CH₂F OH H 1 2-249 CH₂OH CH₂OH H CH₂OH F H 1 2-250 CH₂OH CH₃ H CH₂OH FH 1 2-251 CH₂OH CH₂F H CH₂OH F H 1 2-252 CH₂OH CH₂OCH₃ H CH₂OH F H 12-253 CH₂OH CH₂OCH₃ H CH₂F OH H 1 2-254 CH₂OH CH₂OH H CH₂F F H 1 2-255CH₂OH CH₃ H CH₂F F H 1 2-256 CH₂OH CH₂F H CH₂F F H 1 2-257 CH₂OH CH₂OCH₃H CH₂F F H 1 2-258 CH₂OH CH₂OH CH₃ CH₂OH OH OH 1 2-259 CH₂OH CH₂OH HCH₂OH OH OH 1 2-260 CH₂OH CH₃ H CH₂OH OH OH 1 2-261 CH₂OH CH₂F H CH₂OHOH OH 1 2-262 CH₂OH CH₂OCH₃ H CH₂OH OH OH 1 2-263 CH₂OH CH₃ CH₃ CH₂OH OHOH 1 2-264 CH₂OH CH₂F CH₃ CH₂OH OH OH 1 2-265 CH₂OH CH₂OCH₃ CH₃ CH₂OH OHOH 1 2-266 CH₂OH CH₂OH H CH₂F OH OH 1 2-267 CH₂OH CH₃ H CH₂F OH OH 12-268 CH₂OH CH₂F H CH₂F OH OH 1 2-269 CH₂OH CH₂OCH₃ H CH₂F OH OH 1 2-270CH₂OH CH₂OH H CH₂OH F OH 1 2-271 CH₂OH CH₃ H CH₂OH F OH 1 2-272 CH₂OHCH₂F H CH₂OH F OH 1 2-273 CH₂OH CH₂OCH₃ H CH₂OH F OH 1 2-274 CH₂OH CH₂OHH CH₂F F OH 1 2-275 CH₂OH CH₃ H CH₂F F OH 1 2-276 CH₂OH CH₂F H CH₂F F OH1 2-277 CH₂OH CH₂OCH₃ H CH₂F F OH 1 2-278 CH₂F CH₂OH H CH₂OH OH H 12-279 CH₂F CH₃ H CH₂OH OH H 1 2-280 CH₂F CH₂F H CH₂OH OH H 1 2-281 CH₂FCH₂OCH₃ H CH₂OH OH H 1 2-282 CH₂F CH₂CH₃ H CH₂OH OH H 1 2-283 CH₂FCH₂OCH₂CH₃ H CH₂OH OH H 1 2-284 CH₂F CH₂O^(i)Pr H CH₂OH OH H 1 2-285CH₂F CH₂O^(t)Bu H CH₂OH OH H 1 2-286 CH₂F CH₂OH H CH₃ OH H 1 2-287 CH₂FCH₂OH H CH₂CH₃ OH H 1 2-288 CH₂F CH₂OH H CH₂Br OH H 1 2-289 CH₂F CH₂OH HCH₂Cl OH H 1 2-290 CH₂F CH₂OH H CH₂I OH H 1 2-291 CH₂F CH₂OH H OH OH H 12-292 CH₂F CH₂OH H H OH H 1 2-293 CH₂F CH₂OH H F OH H 1 2-294 CH₂F CH₂OHH CH₂OH CH₃ H 1 2-295 CH₂F CH₂OH H CH₂OH CH₂CH₃ H 1 2-296 CH₂F CH₂OH HCH₂OH CH₂OH H 1 2-297 CH₂F CH₂OH H CH₂OH CH₂F H 1 2-298 CH₂F CH₂OH HCH₂OH H H 1 2-299 CH₂F CH₂OH H CH₂OH OCH₃ H 1 2-300 CH₂F CH₂OH H CH₂OHOCH₂CH₃ H 1 2-301 CH₂F CH₂OH H CH₂OH Br H 1 2-302 CH₂F CH₂OH H CH₂OH ClH 1 2-303 CH₂F CH₂OH H CH₂OH I H 1 2-304 CH₂F CH₂OH H CH₂OH OH CH₃ 12-305 CH₂F CH₂OH H CH₂OH OH CH₂CH₃ 1 2-306 CH₂F CH₂OH H CH₂OH OH CH₂F 12-307 CH₂F CH₂OH H CH₂OH OH OCH₃ 1 2-308 CH₂F CH₂OH H CH₂OH OH OCH₂CH₃ 12-309 CH₂F CH₂OH H CH₂OH OH F 1 2-310 CH₂F CH₂OH CH₃ CH₂OH OH H 1 2-311CH₂F CH₃ CH₃ CH₂OH OH H 1 2-312 CH₂F CH₂F CH₃ CH₂OH OH H 1 2-313 CH₂FCH₂OCH₃ CH₃ CH₂OH OH H 1 2-314 CH₂F CH₂OH H CH₂F OH H 1 2-315 CH₂F CH₃ HCH₂F OH H 1 2-316 CH₂F CH₂F H CH₂F OH H 1 2-317 CH₂F CH₂OH H CH₂OH F H 12-318 CH₂F CH₂OCH₃ H CH₂F OH H 1 2-319 CH₂F CH₃ H CH₂OH F H 1 2-320 CH₂FCH₂F H CH₂OH F H 1 2-321 CH₂F CH₂OCH₃ H CH₂OH F H 1 2-322 CH₂F CH₂OH HCH₂OH OH OH 1 2-323 CH₂F CH₃ H CH₂OH OH OH 1 2-324 CH₂F CH₂F H CH₂OH OHOH 1 2-325 CH₂F CH₂OCH₃ H CH₂OH OH OH 1 2-326 CH₂F CH₂OH CH₃ CH₂OH OH OH1 2-327 CH₂F CH₃ CH₃ CH₂OH OH OH 1 2-328 CH₂F CH₂F CH₃ CH₂OH OH OH 12-329 CH₂F CH₂OCH₃ CH₃ CH₂OH OH OH 1 2-330 CH₂F CH₂OH H CH₂F OH OH 12-331 CH₂F CH₃ H CH₂F OH OH 1 2-332 CH₂F CH₂F H CH₂F OH OH 1 2-333 CH₂FCH₂OCH₃ H CH₂F OH OH 1 2-334 CH₂F CH₂OH H CH₂F F H 1 2-335 CH₂F CH₃ HCH₂F F H 1 2-336 CH₂F CH₂F H CH₂F F H 1 2-337 CH₂F CH₂OCH₃ H CH₂F F H 12-338 CH₂F CH₂OH H CH₂F F OH 1 2-339 CH₂F CH₃ H CH₂F F OH 1 2-340 CH₂FCH₂F H CH₂F F OH 1 2-341 CH₂F CH₂OCH₃ H CH₂F F OH 1 2-342 CH₂F CH₂OH HCH₂OH F OH 1 2-343 CH₂F CH₃ H CH₂OH F OH 1 2-344 CH₂F CH₂F H CH₂OH F OH1 2-345 CH₂F CH₂OCH₃ H CH₂OH F OH 1 2-346 CH₂OCH₃ CH₂OH H CH₂F OH H 12-347 CH₂OCH₃ CH₃ H CH₂F OH H 1 2-348 CH₂OCH₃ CH₂F H CH₂F OH H 1 2-349CH₂OCH₃ CH₂OCH₃ H CH₂F OH H 1 2-350 CH₂OCH₃ CH₂OH H CH₂OH F H 1 2-351CH₂OCH₃ CH₃ H CH₂OH F H 1 2-352 CH₂OCH₃ CH₂F H CH₂OH F H 1 2-353 CH₂OCH₃CH₂OCH₃ H CH₂OH F H 1 2-354 CH₂OCH₃ CH₂OH H CH₂OH OH H 1 2-355 CH₂OCH₃CH₃ H CH₂OH OH H 1 2-356 CH₂OCH₃ CH₂F H CH₂OH OH H 1 2-357 CH₂OCH₃CH₂OCH₃ H CH₂OH OH H 1 2-358 CH₂OCH₃ CH₃ H CH₂OH OH H 1 2-359 CH₂OCH₃CH₂F H CH₂OH OH H 1 2-360 CH₂OCH₃ CH₂OCH₃ H CH₂OH OH H 1 2-361 CH₂OCH₃CH₂CH₃ H CH₂OH OH H 1 2-362 CH₂OCH₃ CH₂OCH₂CH₃ H CH₂OH OH H 1 2-363CH₂OCH₃ CH₂O^(i)Pr H CH₂OH OH H 1 2-364 CH₂OCH₃ CH₂O^(t)Bu H CH₂OH OH H1 2-365 CH₂OCH₃ CH₂OH H CH₃ OH H 1 2-366 CH₂OCH₃ CH₂OH H CH₂CH₃ OH H 12-367 CH₂OCH₃ CH₂OH H OH OH H 1 2-368 CH₂OCH₃ CH₂OH H H OH H 1 2-369CH₂OCH₃ CH₂OH H F OH H 1 2-370 CH₂OCH₃ CH₂OH H CH₂OH CH₃ H 1 2-371CH₂OCH₃ CH₂OH H CH₂OH CH₂CH₃ H 1 2-372 CH₂OCH₃ CH₂OH H CH₂OH CH₂OH H 12-373 CH₂OCH₃ CH₂OH H CH₂OH CH₂F H 1 2-374 CH₂OCH₃ CH₂OH H CH₂OH H H 12-375 CH₂OCH₃ CH₂OH H CH₂OH OCH₃ H 1 2-376 CH₂OCH₃ CH₂OH H CH₂OH OCH₂CH₃H 1 2-377 CH₂OCH₃ CH₂OH H CH₂OH Br H 1 2-378 CH₂OCH₃ CH₂OH H CH₂OH Cl H1 2-379 CH₂OCH₃ CH₂OH H CH₂OH I H 1 2-380 CH₂OCH₃ CH₂OH H CH₂OH OH CH₃ 12-381 CH₂OCH₃ CH₂OH H CH₂OH OH CH₂CH₃ 1 2-382 CH₂OCH₃ CH₂OH H CH₂OH OHCH₂F 1 2-383 CH₂OCH₃ CH₂OH H CH₂OH OH OCH₃ 1 2-384 CH₂OCH₃ CH₂OH H CH₂OHOH OCH₂CH₃ 1 2-385 CH₂OCH₃ CH₂OH H CH₂OH OH F 1 2-386 CH₂OCH₃ CH₂OH CH₃CH₂OH OH H 1 2-387 CH₂OCH₃ CH₃ CH₃ CH₂OH OH H 1 2-388 CH₂OCH₃ CH₂F CH₃CH₂OH OH H 1 2-389 CH₂OCH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 2-390 CH₂OCH₃ CH₂OHH CH₂F F H 1 2-391 CH₂OCH₃ CH₃ H CH₂F F H 1 2-392 CH₂OCH₃ CH₂F H CH₂F FH 1 2-393 CH₂OCH₃ CH₂OCH₃ H CH₂F F H 1 2-394 CH₂OCH₃ CH₂OH CH₃ CH₂OH OHOH 1 2-395 CH₂OCH₃ CH₃ CH₃ CH₂OH OH OH 1 2-396 CH₂OCH₃ CH₂F CH₃ CH₂OH OHOH 1 2-397 CH₂OCH₃ CH₃OCH₃ CH₃ CH₃OH OH OH 1 2-398 CH₂OCH₃ CH₂OH H CH₂FOH OH 1 2-399 CH₂OCH₃ CH₃ H CH₂F OH OH 1 2-400 CH₂OCH₃ CH₂F H CH₂F OH OH1 2-401 CH₂OCH₃ CH₂OCH₃ H CH₂F OH OH 1 2-402 CH₂OCH₃ CH₂OH H CH₂OH F OH1 2-403 CH₂OCH₃ CH₃ H CH₂OH F OH 1 2-404 CH₂OCH₃ CH₂F H CH₂OH F OH 12-405 CH₂OCH₃ CH₂OCH₃ H CH₂OH F OH 1 2-406 CH₂OCH₃ CH₂OH H CH₂F F OH 12-407 CH₂OCH₃ CH₃ H CH₂F F OH 1 2-408 CH₂OCH₃ CH₂F H CH₂F F OH 1 2-409CH₂OCH₃ CH₂OCH₃ H CH₂F F OH 1 2-410 CH₂OCH₂CH₃ CH₂OH H CH₂OH OH H 12-411 CH₂OCH₂CH₃ CH₃ H CH₂OH OH H 1 2-412 CH₂OCH₂CH₃ CH₂F H CH₂OH OH H 12-413 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH OH H 1 2-414 CH₂OCH₂CH₃ CH₂OH CH₃ CH₂OHOH H 1 2-415 CH₂OCH₂CH₃ CH₃ CH₃ CH₂OH OH H 1 2-416 CH₂OCH₂CH₃ CH₂F CH₃CH₂OH OH H 1 2-417 CH₂OCH₂CH₃ CH₂OCH₃ CH₃ CH₂OH OH H 1 2-418 CH₂OCH₂CH₃CH₂OH H CH₂F OH H 1 2-419 CH₂OCH₂CH₃ CH₃ H CH₂F OH H 1 2-420 CH₂OCH₂CH₃CH₂F H CH₂F OH H 1 2-421 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F OH H 1 2-422CH₂OCH₂CH₃ CH₂OH H CH₂OH F H 1 2-423 CH₂OCH₂CH₃ CH₃ H CH₂OH F H 1 2-424CH₂OCH₂CH₃ CH₂F H CH₂OH F H 1 2-425 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH F H 12-426 CH₂OCH₂CH₃ CH₂OH H CH₂F F H 1 2-427 CH₂OCH₂CH₃ CH₃ H CH₂F F H 12-428 CH₂OCH₂CH₃ CH₂F H CH₂F F H 1 2-429 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F F H 12-430 CH₂OCH₂CH₃ CH₂OH H CH₂OH OH OH 1 2-431 CH₂OCH₂CH₃ CH₃ H CH₂OH OHOH 1 2-432 CH₂OCH₂CH₃ CH₂F H CH₂OH OH OH 1 2-433 CH₂OCH₂CH₃ CH₂OCH₃ HCH₂OH OH OH 1 2-434 CH₂OCH₂CH₃ CH₂OH CH₃ CH₂OH OH OH 1 2-435 CH₂OCH₂CH₃CH₃ CH₃ CH₂OH OH OH 1 2-436 CH₂OCH₂CH₃ CH₂F CH₃ CH₂OH OH OH 1 2-437CH₂OCH₂CH₃ CH₂OCH₃ CH₃ CH₂OH OH OH 1 2-438 CH₂OCH₂CH₃ CH₂OH H CH₂F OH OH1 2-439 CH₂OCH₂CH₃ CH₃ H CH₂F OH OH 1 2-440 CH₂OCH₂CH₃ CH₂F H CH₂F OH OH1 2-441 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F OH OH 1 2-442 CH₂OCH₂CH₃ CH₂OH H CH₂OHF OH 1 2-443 CH₂OCH₂CH₃ CH₃ H CH₂OH F OH 1 2-444 CH₂OCH₂CH₃ CH₂F H CH₂OHF OH 1 2-445 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂OH F OH 1 2-446 CH₂OCH₂CH₃ CH₂OH HCH₂F F OH 1 2-447 CH₂OCH₂CH₃ CH₃ H CH₂F F OH 1 2-448 CH₂OCH₂CH₃ CH₂F HCH₂F F OH 1 2-449 CH₂OCH₂CH₃ CH₂OCH₃ H CH₂F F OH 1 2-450 CH₂O^(n)PrCH₂OH H CH₂OH OH H 1 2-451 CH₂O^(i)Pr CH₂OH H CH₂OH OH H 1 2-452CH₂O^(n)Bu CH₂OH H CH₂OH OH H 1 2-453 CH₂O^(i)Bu CH₂OH H CH₂OH OH H 12-454 CH₂O^(t)Bu CH₂OH H CH₂OH OH H 1 2-455 CH₂O^(n)Pn CH₂OH H CH₂OH OHH 1 2-456 CH₂O^(n)Hex CH₂OH H CH₂OH OH H 1 2-457 CH₂Cl CH₂OH H CH₂OH OHH 1 2-458 CH₂Cl CH₃ H CH₂OH OH H 1 2-459 CH₂Cl CH₂F H CH₂OH OH H 1 2-460CH₂Cl CH₂OCH₃ H CH₂OH OH H 1 2-461 CH₂Cl CH₂OH CH₃ CH₂OH OH H 1 2-462CH₂Cl CH₃ CH₃ CH₂OH OH H 1 2-463 CH₂Cl CH₂F CH₃ CH₂OH OH H 1 2-464 CH₂ClCH₂OCH₃ CH₃ CH₂OH OH H 1 2-465 CH₂Cl CH₃OH H CH₂F OH H 1 2-466 CH₂Cl CH₃H CH₂F OH H 1 2-467 CH₂Cl CH₂F H CH₂F OH H 1 2-468 CH₂Cl CH₂OCH₃ H CH₂FOH H 1 2-469 CH₂Cl CH₂OH H CH₂OH F H 1 2-470 CH₂Cl CH₃ H CH₂OH F H 12-471 CH₂Cl CH₂F H CH₂OH F H 1 2-472 CH₂Cl CH₂OCH₃ H CH₂OH F H 1 2-473CH₂Cl CH₂OH H CH₂F F H 1 2-474 CH₂Cl CH₃ H CH₂F F H 1 2-475 CH₂Cl CH₂F HCH₂F F H 1 2-476 CH₂Cl CH₂OCH₃ H CH₂F F H 1 2-477 CH₂Cl CH₂OH H CH₂OH OHOH 1 2-478 CH₂Cl CH₃ H CH₂OH OH OH 1 2-479 CH₂Cl CH₂F H CH₂OH OH OH 12-480 CH₂Cl CH₂OCH₃ H CH₂OH OH OH 1 2-481 CH₂Cl CH₂OH H CH₂F OH OH 12-482 CH₂Cl CH₃ H CH₂F OH OH 1 2-483 CH₂Cl CH₂F H CH₂F OH OH 1 2-484CH₂Cl CH₂OCH₃ H CH₂F OH OH 1 2-485 CH₂Cl CH₂OH H CH₂OH F OH 1 2-486CH₂Cl CH₃ H CH₂OH F OH 1 2-487 CH₂Cl CH₂F H CH₂OH F OH 1 2-488 CH₂ClCH₂OCH₃ H CH₂OH F OH 1 2-489 CH₂Cl CH₂OH H CH₂F F OH 1 2-490 CH₂Cl CH₃ HCH₂F F OH 1 2-491 CH₂Cl CH₂F H CH₂F F OH 1 2-492 CH₂Cl CH₂OCH₃ H CH₂F FOH 1 2-493 CH₂Cl CH₂OH CH₃ CH₂OH OH OH 1 2-494 CH₂Cl CH₃ CH₃ CH₂OH OH OH1 2-495 CH₂Cl CH₂F CH₃ CH₂OH OH OH 1 2-496 CH₂Cl CH₂OCH₃ CH₃ CH₂OH OH OH1 2-497 CH₂Br CH₂OH H CH₂OH OH H 1 2-498 CH₂Br CH₃ H CH₂OH OH H 1 2-499CH₂Br CH₂F H CH₂OH OH H 1 2-500 CH₂Br CH₂OCH₃ H CH₂OH OH H 1 2-501 CH₂BrCH₂OH CH₃ CH₂OH OH H 1 2-502 CH₂Br CH₃ CH₃ CH₂OH OH H 1 2-503 CH₂Br CH₂FCH₃ CH₂OH OH H 1 2-504 CH₂Br CH₂OCH₃ CH₃ CH₂OH OH H 1 2-505 CH₂Br CH₂OHH CH₂F OH H 1 2-506 CH₂Br CH₃ H CH₂F OH H 1 2-507 CH₂Br CH₂F H CH₂F OH H1 2-508 CH₂Br CH₂OCH₃ H CH₂F OH H 1 2-509 CH₂Br CH₂OH H CH₂OH F H 12-510 CH₂Br CH₃ H CH₂OH F H 1 2-511 CH₂Br CH₂F H CH₂OH F H 1 2-512 CH₂BrCH₂OCH₃ H CH₂OH F H 1 2-513 CH₂Br CH₂OH H CH₂F F H 1 2-514 CH₂Br CH₃ HCH₂F F H 1 2-515 CH₂Br CH₂F H CH₂F F H 1 2-516 CH₂Br CH₂OCH₃ H CH₂F F H1 2-517 CH₂Br CH₂OH H CH₂OH OH OH 1 2-518 CH₂Br CH₃ H CH₂OH OH OH 12-519 CH₂Br CH₂F H CH₂OH OH OH 1 2-520 CH₂Br CH₂OH CH₃ CH₂OH OH OH 12-521 CH₂Br CH₃ CH₃ CH₂OH OH OH 1 2-522 CH₂Br CH₂F CH₃ CH₂OH OH OH 12-523 CH₂Br CH₂OCH₃ CH₃ CH₂OH OH OH 1 2-524 CH₂Br CH₂OH H CH₂F OH OH 12-525 CH₂Br CH₃ H CH₂F OH OH 1 2-526 CH₂Br CH₂F H CH₂F OH OH 1 2-527CH₂Br CH₂OCH₃ H CH₂F OH OH 1 2-528 CH₂Br CH₂OH H CH₂OH F OH 1 2-529CH₂Br CH₃ H CH₂OH F OH 1 2-530 CH₂Br CH₂F H CH₂OH F OH 1 2-531 CH₂BrCH₂OCH₃ H CH₂OH F OH 1 2-532 CH₂Br CH₂OH H CH₂F F OH 1 2-533 CH₂Br CH₃ HCH₂F F OH 1 2-534 CH₂Br CH₂F H CH₂F F OH 1 2-535 CH₂Br CH₂OCH₃ H CH₂F FOH 1 2-536 CH₂Br CH₂OCH₃ H CH₂OH OH OH 1 2-537 CH₂I CH₂OH H CH₂OH OH H 12-538 CH₃ CH₂OH H CH₂OH OH H 2 2-539 CH₃ CH₃ H CH₂OH OH H 2 2-540 CH₃CH₂F H CH₂OH OH H 2 2-541 CH₃ CH₂OH H CH₂OH F H 2 2-542 CH₃ CH₃ H CH₂OHF H 2 2-543 CH₃ CH₂F H CH₂OH F H 2 2-544 CH₃ CH₂OH H CH₂F OH H 2 2-545CH₃ CH₃ H CH₂F OH H 2 2-546 CH₃ CH₂F H CH₂F OH H 2 2-547 CH₂OH CH₂OH HCH₂OH OH H 2 2-548 CH₂OH CH₃ H CH₂OH OH H 2 2-549 CH₂OH CH₂F H CH₂OH OHH 2 2-550 CH₂F CH₂OH H CH₂OH OH H 2 2-551 CH₂F CH₃ H CH₂OH OH H 2 2-552CH₂F CH₂F H CH₂OH OH H 2 2-553 CH₂OCH₃ CH₂OH H CH₂OH OH H 2 2-554CH₂OCH₃ CH₃ H CH₂OH OH H 2 2-555 CH₂OCH₃ CH₂F H CH₂OH OH H 2

TABLE 3 (Ib′)

No. R¹ R² R³ R⁴ n 3-1  CH₃ CH₂OH CH₂OH OH 1 3-2  CH₃ CH₃ CH₂OH OH 1 3-3 CH₃ CH₂F CH₂OH OH 1 3-4  CH₃ CH₂OCH₃ CH₂OH OH 1 3-5  CH₃ CH₂OH CH₂F OH 13-6  CH₃ CH₃ CH₂F OH 1 3-7  CH₃ CH₂F CH₂F OH 1 3-8  CH₃ CH₂OCH₃ CH₂F OH1 3-9  CH₃ CH₂OH CH₂OH CH₂OH 1 3-10 CH₃ CH₃ CH₂OH CH₂OH 1 3-11 CH₃ CH₂OHCH₂OH F 1 3-12 CH₃ CH₃ CH₂OH F 1 3-13 CH₃ CH₂F CH₂OH F 1 3-14 CH₃CH₂OCH₃ CH₂OH F 1 3-15 CH₃ CH₂OH CH₂F F 1 3-16 CH₃ CH₃ CH₂F F 1 3-17 CH₃CH₂F CH₂F F 1 3-18 CH₃ CH₂OCH₃ CH₂F F 1 3-19 CH₃ CH₂OH CH₂OH Cl 1 3-20CH₃ CH₃ CH₂OH Cl 1 3-21 CH₃ CH₂OH CH₂OH Br 1 3-22 CH₃ CH₃ CH₂OH Br 13-23 CH₃ CH₂OH CH₂OH I 1 3-24 CH₃ CH₃ CH₂OH I 1 3-25 CH₂CH₃ CH₂OH CH₂OHOH 1 3-26 ^(n)Pr CH₂OH CH₂OH OH 1 3-27 ^(i)Pr CH₂OH CH₂OH OH 1 3-28^(n)Bu CH₂OH CH₂OH OH 1 3-29 ^(i)Bu CH₂OH CH₂OH OH 1 3-30 ^(t)Bu CH₂OHCH₂OH OH 1 3-31 ^(n)Pn CH₂OH CH₂OH OH 1 3-32 ^(n)Hex CH₂OH CH₂OH OH 13-33 CH₂OH CH₂OH CH₂OH OH 1 3-34 CH₂OH CH₃ CH₂OH OH 1 3-35 CH₂OH CH₂FCH₂OH OH 1 3-36 CH₂OH CH₂OCH₃ CH₂OH OH 1 3-37 CH₂OH CH₂OH CH₂F OH 1 3-38CH₂OH CH₃ CH₂F OH 1 3-39 CH₂OH CH₂F CH₂F OH 1 3-40 CH₂OH CH₂OCH₃ CH₂F OH1 3-41 CH₂OH CH₂OH CH₂OH F 1 3-42 CH₂OH CH₃ CH₂OH F 1 3-43 CH₂OH CH₂FCH₂OH F 1 3-44 CH₂OH CH₂OCH₃ CH₂OH F 1 3-45 CH₂OH CH₂OH CH₂F F 1 3-46CH₂OH CH₃ CH₂F F 1 3-47 CH₂OH CH₂F CH₂F F 1 3-48 CH₂OH CH₂OCH₃ CH₂F F 13-49 CH₂OCH₃ CH₂OH CH₂OH OH 1 3-50 CH₂OCH₃ CH₃ CH₂OH OH 1 3-51 CH₂OCH₃CH₂F CH₂OH OH 1 3-52 CH₂OCH₃ CH₂OCH₃ CH₂OH OH 1 3-53 CH₂OCH₃ CH₂OH CH₂FOH 1 3-54 CH₂OCH₃ CH₃ CH₂F OH 1 3-55 CH₂OCH₃ CH₂F CH₂F OH 1 3-56 CH₂OCH₃CH₂OCH₃ CH₂F OH 1 3-57 CH₂OCH₃ CH₂OH CH₂OH F 1 3-58 CH₂OCH₃ CH₃ CH₂OH F1 3-59 CH₂OCH₃ CH₂F CH₂OH F 1 3-60 CH₂OCH₃ CH₂OCH₃ CH₂OH F 1 3-61CH₂OCH₃ CH₂OH CH₂F F 1 3-62 CH₂OCH₃ CH₃ CH₂F F 1 3-63 CH₂OCH₃ CH₂F CH₂FF 1 3-64 CH₂OCH₃ CH₂OCH₃ CH₂F F 1 3-65 CH₂OCH₂CH₃ CH₂OH CH₂OH OH 1 3-66CH₂OCH₂CH₃ CH₃ CH₂OH OH 1 3-67 CH₂OCH₂CH₃ CH₂F CH₂OH OH 1 3-68CH₂OCH₂CH₃ CH₂OCH₃ CH₂OH OH 1 3-69 CH₂OCH₂CH₃ CH₂OH CH₂F OH 1 3-70CH₂OCH₂CH₃ CH₃ CH₂F OH 1 3-71 CH₂OCH₂CH₃ CH₂F CH₂F OH 1 3-72 CH₂OCH₂CH₃CH₂OCH₃ CH₂F OH 1 3-73 CH₂OCH₂CH₃ CH₂OH CH₂OH F 1 3-74 CH₂OCH₂CH₃ CH₃CH₂OH F 1 3-75 CH₂OCH₂CH₃ CH₂F CH₂OH F 1 3-76 CH₂OCH₂CH₃ CH₂OCH₃ CH₂OH F1 3-77 CH₂OCH₂CH₃ CH₂OH CH₂F F 1 3-78 CH₂OCH₂CH₃ CH₃ CH₂F F 1 3-79CH₂OCH₂CH₃ CH₂F CH₂F F 1 3-80 CH₂OCH₂CH₃ CH₂OCH₃ CH₂F F 1 3-81CH₂OCH₂CH₃ CH₂OH CH₂F F 1 3-82 CH₂OCH₂CH₃ CH₃ CH₂F F 1 3-83 CH₂OCH₂CH₃CH₂F CH₂F F 1 3-84 CH₂OCH₂CH₃ CH₂OCH₃ CH₂F F 1 3-85 CH₂O^(n)Pr CH₂OHCH₂OH OH 1 3-86 CH₂O^(i)Pr CH₂OH CH₂OH OH 1 3-87 CH₂O^(n)Bu CH₂OH CH₂OHOH 1 3-88 CH₂O^(i)Bu CH₂OH CH₂OH OH 1 3-89 CH₂O^(t)Bu CH₂OH CH₂OH OH 13-90 CH₂O^(n)Pn CH₂OH CH₂OH OH 1 3-91 CH₂O^(n)Hex CH₂OH CH₂OH OH 1 3-92CH₂F CH₂OH CH₂OH OH 1 3-93 CH₂F CH₃ CH₂OH OH 1 3-94 CH₂F CH₂F CH₂OH OH 13-95 CH₂F CH₂OCH₃ CH₂OH OH 1 3-96 CH₂F CH₂OH CH₂F OH 1 3-97 CH₂F CH₃CH₂F OH 1 3-98 CH₂F CH₂F CH₂F OH 1 3-99 CH₂F CH₂OCH₃ CH₂F OH 1  3-100CH₂F CH₂OH CH₂OH F 1  3-101 CH₂F CH₃ CH₂OH F 1  3-102 CH₂F CH₂F CH₂OH F1  3-103 CH₂F CH₂OCH₃ CH₂OH F 1  3-104 CH₂F CH₂OH CH₂F F 1  3-105 CH₂FCH₃ CH₂F F 1  3-106 CH₂F CH₂F CH₂F F 1  3-107 CH₂F CH₂OCH₃ CH₂F F 1 3-108 CH₂Cl CH₂OH CH₂OH OH 1  3-109 CH₂Cl CH₃ CH₂OH OH 1  3-110 CH₂ClCH₂F CH₂OH OH 1  3-111 CH₂Cl CH₂OCH₃ CH₂OH OH 1  3-112 CH₂Cl CH₂OH CH₂FOH 1  3-113 CH₂Cl CH₃ CH₂F OH 1  3-114 CH₂Cl CH₂F CH₂F OH 1  3-115 CH₂ClCH₂OCH₃ CH₂F OH 1  3-116 CH₂Cl CH₂OH CH₂OH F 1  3-117 CH₂Cl CH₃ CH₂OH F1  3-118 CH₂Cl CH₂F CH₂OH F 1  3-119 CH₂Cl CH₂OCH₃ CH₂OH F 1  3-120CH₂Cl CH₂OH CH₂F F 1  3-121 CH₂Cl CH₃ CH₂F F 1  3-122 CH₂Cl CH₂F CH₂F F1  3-123 CH₂Cl CH₂OCH₃ CH₂F F 1  3-124 CH₂Br CH₂OH CH₂OH OH 1  3-125CH₂Br CH₃ CH₂OH OH 1  3-126 CH₂Br CH₂F CH₂OH OH 1  3-127 CH₂Br CH₂OCH₃CH₂OH OH 1  3-128 CH₂Br CH₂OH CH₂F OH 1  3-129 CH₂Br CH₃ CH₂F OH 1 3-130 CH₂Br CH₂F CH₂F OH 1  3-131 CH₂Br CH₂OCH₃ CH₂F OH 1  3-132 CH₂BrCH₂OH CH₂OH F 1  3-133 CH₂Br CH₃ CH₂OH F 1  3-134 CH₂Br CH₂F CH₂OH F 1 3-135 CH₂Br CH₂OCH₃ CH₂OH F 1  3-136 CH₂Br CH₂OH CH₂F F 1  3-137 CH₂BrCH₃ CH₂F F 1  3-138 CH₂Br CH₂F CH₂F F 1  3-139 CH₂Br CH₂OCH₃ CH₂F F 1 3-140 CH₂I CH₂OH CH₂OH OH 1  3-141 CH₂I CH₃ CH₂OH OH 1  3-142 CH₂I CH₂FCH₂OH OH 1  3-143 CH₃ CH₂OH CH₂OH OH 2  3-144 CH₃ CH₃ CH₂OH OH 2  3-145CH₃ CH₂F CH₂OH OH 2  3-146 CH₃ CH₂OCH₃ CH₂OH OH 2  3-147 CH₂OH CH₂OHCH₂OH OH 2  3-148 CH₂OH CH₃ CH₂OH OH 2  3-149 CH₂OH CH₂F CH₂OH OH 2 3-150 CH₂OH CH₂OCH₃ CH₂OH OH 2

TABLE 4 (Ib″)

No. R¹ R² R³ R⁴ n 4-1  CH₃ CH₂OH CH₂OH OH 1 4-2  CH₃ CH₃ CH₂OH OH 1 4-3 CH₃ CH₂F CH₂OH OH 1 4-4  CH₃ CH₂OCH₃ CH₂OH OH 1 4-5  CH₃ CH₂OH CH₂F OH 14-6  CH₃ CH₃ CH₂F OH 1 4-7  CH₃ CH₂F CH₂F OH 1 4-8  CH₃ CH₂OCH₃ CH₂F OH1 4-9  CH₃ CH₂OH CH₂OH CH₂OH 1 4-10 CH₃ CH₃ CH₂OH CH₂OH 1 4-11 CH₃ CH₂OHCH₂OH F 1 4-12 CH₃ CH₃ CH₂OH F 1 4-13 CH₃ CH₂F CH₂OH F 1 4-14 CH₃CH₂OCH₃ CH₂OH F 1 4-15 CH₃ CH₂OH CH₂F F 1 4-16 CH₃ CH₃ CH₂F F 1 4-17 CH₃CH₂F CH₂F F 1 4-18 CH₃ CH₂OCH₃ CH₂F F 1 4-19 CH₃ CH₂OH CH₂OH Cl 1 4-20CH₃ CH₃ CH₂OH Cl 1 4-21 CH₃ CH₂OH CH₂OH Br 1 4-22 CH₃ CH₃ CH₂OH Br 14-23 CH₃ CH₂OH CH₂OH I 1 4-24 CH₃ CH₃ CH₂OH I 1 4-25 CH₂CH₃ CH₂OH CH₂OHOH 1 4-26 ^(n)Pr CH₂OH CH₂OH OH 1 4-27 ^(i)Pr CH₂OH CH₂OH OH 1 4-28^(n)Bu CH₂OH CH₂OH OH 1 4-29 ^(i)Bu CH₂OH CH₂OH OH 1 4-30 ^(t)Bu CH₂OHCH₂OH OH 1 4-31 ^(n)Pn CH₂OH CH₂OH OH 1 4-32 ^(n)Hex CH₂OH CH₂OH OH 14-33 CH₂OH CH₂OH CH₂OH OH 1 4-34 CH₂OH CH₃ CH₂OH OH 1 4-35 CH₂OH CH₂FCH₂OH OH 1 4-36 CH₂OH CH₂OCH₃ CH₂OH OH 1 4-37 CH₂OH CH₂OH CH₂F OH 1 4-38CH₂OH CH₃ CH₂F OH 1 4-39 CH₂OH CH₂F CH₂F OH 1 4-40 CH₂OH CH₂OCH₃ CH₂F OH1 4-41 CH₂OH CH₂OH CH₂OH F 1 4-42 CH₂OH CH₃ CH₂OH F 1 4-43 CH₂OH CH₂FCH₂OH F 1 4-44 CH₂OH CH₂OCH₃ CH₂OH F 1 4-45 CH₂OH CH₂OH CH₂F F 1 4-46CH₂OH CH₃ CH₂F F 1 4-47 CH₂OH CH₂F CH₂F F 1 4-48 CH₂OH CH₂OCH₃ CH₂F F 14-49 CH₂OCH₃ CH₂OH CH₂OH OH 1 4-50 CH₂OCH₃ CH₃ CH₂OH OH 1 4-51 CH₂OCH₃CH₂F CH₂OH OH 1 4-52 CH₂OCH₃ CH₂OCH₃ CH₂OH OH 1 4-53 CH₂OCH₃ CH₂OH CH₂FOH 1 4-54 CH₂OCH₃ CH₃ CH₂F OH 1 4-55 CH₂OCH₃ CH₂F CH₂F OH 1 4-56 CH₂OCH₃CH₂OCH₃ CH₂F OH 1 4-57 CH₂OCH₃ CH₂OH CH₂OH F 1 4-58 CH₂OCH₃ CH₃ CH₂OH F1 4-59 CH₂OCH₃ CH₂F CH₂OH F 1 4-60 CH₂OCH₃ CH₂OCH₃ CH₂OH F 1 4-61CH₂OCH₃ CH₂OH CH₂F F 1 4-62 CH₂OCH₃ CH₃ CH₂F F 1 4-63 CH₂OCH₃ CH₂F CH₂FF 1 4-64 CH₂OCH₃ CH₂OCH₃ CH₂F F 1 4-65 CH₂OCH₂CH₃ CH₂OH CH₂OH OH 1 4-66CH₂OCH₂CH₃ CH₃ CH₂OH OH 1 4-67 CH₂OCH₂CH₃ CH₂F CH₂OH OH 1 4-68CH₂OCH₂CH₃ CH₂OCH₃ CH₂OH OH 1 4-69 CH₂OCH₂CH₃ CH₂OH CH₂F OH 1 4-70CH₂OCH₂CH₃ CH₃ CH₂F OH 1 4-71 CH₂OCH₂CH₃ CH₂F CH₂F OH 1 4-72 CH₂OCH₂CH₃CH₂OCH₃ CH₂F OH 1 4-73 CH₂OCH₂CH₃ CH₂OH CH₂OH F 1 4-74 CH₂OCH₂CH₃ CH₃CH₂OH F 1 4-75 CH₂OCH₂CH₃ CH₂F CH₂OH F 1 4-76 CH₂OCH₂CH₃ CH₂OCH₃ CH₂OH F1 4-77 CH₂OCH₂CH₃ CH₂OH CH₂F F 1 4-78 CH₂OCH₂CH₃ CH₃ CH₂F F 1 4-79CH₂OCH₂CH₃ CH₂F CH₂F F 1 4-80 CH₂OCH₂CH₃ CH₂OCH₃ CH₂F F 1 4-81CH₂OCH₂CH₃ CH₂OH CH₂F F 1 4-82 CH₂OCH₂CH₃ CH₃ CH₂F F 1 4-83 CH₂OCH₂CH₃CH₂F CH₂F F 1 4-84 CH₂OCH₂CH₃ CH₂OCH₃ CH₂F F 1 4-85 CH₂O^(n)Pr CH₂OHCH₂OH OH 1 4-86 CH₂O^(i)Pr CH₂OH CH₂OH OH 1 4-87 CH₂O^(n)Bu CH₂OH CH₂OHOH 1 4-88 CH₂O^(i)Bu CH₂OH CH₂OH OH 1 4-89 CH₂O^(t)Bu CH₂OH CH₂OH OH 14-90 CH₂O^(n)Pn CH₂OH CH₂OH OH 1 4-91 CH₂O^(n)Hex CH₂OH CH₂OH OH 1 4-92CH₂F CH₂OH CH₂OH OH 1 4-93 CH₂F CH₃ CH₂OH OH 1 4-94 CH₂F CH₂F CH₂OH OH 14-95 CH₂F CH₂OCH₃ CH₂OH OH 1 4-96 CH₂F CH₂OH CH₂F OH 1 4-97 CH₂F CH₃CH₂F OH 1 4-98 CH₂F CH₂F CH₂F OH 1 4-99 CH₂F CH₂OCH₃ CH₂F OH 1  4-100CH₂F CH₂OH CH₂OH F 1  4-101 CH₂F CH₃ CH₂OH F 1  4-102 CH₂F CH₂F CH₂OH F1  4-103 CH₂F CH₂OCH₃ CH₂OH F 1  4-104 CH₂F CH₂OH CH₂F F 1  4-105 CH₂FCH₃ CH₂F F 1  4-106 CH₂F CH₂F CH₂F F 1  4-107 CH₂F CH₂OCH₃ CH₂F F 1 4-108 CH₂Cl CH₂OH CH₂OH OH 1  4-109 CH₂Cl CH₃ CH₂OH OH 1  4-110 CH₂ClCH₂F CH₂OH OH 1  4-111 CH₂Cl CH₂OCH₃ CH₂OH OH 1  4-112 CH₂Cl CH₂OH CH₂FOH 1  4-113 CH₂Cl CH₃ CH₂F OH 1  4-114 CH₂Cl CH₂F CH₂F OH 1  4-115 CH₂ClCH₂OCH₃ CH₂F OH 1  4-116 CH₂Cl CH₂OH CH₂OH F 1  4-117 CH₂Cl CH₃ CH₂OH F1  4-118 CH₂Cl CH₂F CH₂OH F 1  4-119 CH₂Cl CH₂OCH₃ CH₂OH F 1  4-120CH₂Cl CH₂OH CH₂F F 1  4-121 CH₂Cl CH₃ CH₂F F 1  4-122 CH₂Cl CH₂F CH₂F F1  4-123 CH₂Cl CH₂OCH₃ CH₂F F 1  4-124 CH₂Br CH₂OH CH₂OH OH 1  4-125CH₂Br CH₃ CH₂OH OH 1  4-126 CH₂Br CH₂F CH₂OH OH 1  4-127 CH₂Br CH₂OCH₃CH₂OH OH 1  4-128 CH₂Br CH₂OH CH₂F OH 1  4-129 CH₂Br CH₃ CH₂F OH 1 4-130 CH₂Br CH₂F CH₂F OH 1  4-131 CH₂Br CH₂OCH₃ CH₂F OH 1  4-132 CH₂BrCH₂OH CH₂OH F 1  4-133 CH₂Br CH₃ CH₂OH F 1  4-134 CH₂Br CH₂F CH₂OH F 1 4-135 CH₂Br CH₂OCH₃ CH₂OH F 1  4-136 CH₂Br CH₂OH CH₂F F 1  4-137 CH₂BrCH₃ CH₂F F 1  4-138 CH₂Br CH₂F CH₂F F 1  4-139 CH₂Br CH₂OCH₃ CH₂F F 1 4-140 CH₂I CH₂OH CH₂OH OH 1  4-141 CH₂I CH₃ CH₂OH OH 1  4-142 CH₂I CH₂FCH₂OH OH 1  4-143 CH₃ CH₂OH CH₂OH OH 2  4-144 CH₃ CH₃ CH₂OH OH 2  4-145CH₃ CH₂F CH₂OH OH 2  4-146 CH₃ CH₂OCH₃ CH₂OH OH 2  4-147 CH₂OH CH₂OHCH₂OH OH 2  4-148 CH₂OH CH₃ CH₂OH OH 2  4-149 CH₂OH CH₂F CH₂OH OH 2 4-150 CH₂OH CH₂OCH₃ CH₂OH OH 2

TABLE 5 (Ic)

R¹ R² R³ R⁴ R⁵ R⁶ n 5-1  CH₃ CH₂OH OH OH NH₂ CH₂OH 1 5-2  CH₃ CH₂F OH OHNH₂ CH₂OH 1 5-3  CH₃ CH₂OH OH CH₂OH NH₂ CH₂OH 1 5-4  CH₃ CH₂F OH CH₂OHNH₂ CH₂OH 1 5-5  CH₃ CH₂OH OH NH₂ H CH₂OH 1 5-6  CH₃ CH₂F OH NH₂ H CH₂OH1 5-7  CH₃ CH₂OH OH NHCH(CH₂OH)₂ H CH₂OH 1 5-8  CH₃ CH₂F OH NHCH(CH₂OH)₂H CH₂OH 1 5-9  CH₃ CH₂OH OH F NH₂ CH₂OH 1 5-10 CH₃ CH₂OH OH OH N(CH₃)₂CH₂OH 1 5-11 CH₃ CH₂OH OH OH NH(CH₃) CH₂OH 1 5-12 CH₃ CH₂OH OH OHN(CH₂CH₃)₂ CH₂OH 1 5-13 CH₃ CH₂OH OH OH NH(CH₂CH₃) CH₂OH 1 5-14 CH₃CH₂OH OH OH NH(^(n)Pr) CH₂OH 1 5-15 CH₃ CH₂OH OH OH NH(^(n)Bu) CH₂OH 15-16 CH₃ CH₂OH OH OH NH(^(i)Bu) CH₂OH 1 5-17 CH₃ CH₂OH OH OH NH(^(t)Bu)CH₂OH 1 5-18 CH₃ CH₂OH OH OH NH(^(n)Pn) CH₂OH 1 5-19 CH₃ CH₂OH OH OHNH(^(n)Hex) CH₂OH 1 5-20 CH₃ CH₂F OH OH NH(CH₂OH) CH₂OH 1 5-21 CH₃ CH₂FOH OH N(CH₂OH)₂ CH₂OH 1 5-22 CH₃ CH₂OH OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-23CH₃ CH₂F OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-24 CH₃ CH₂OH OH OH NH₂ H 1 5-25CH₃ CH₂OH OH OH NH₂ CH₂F 1 5-26 CH₃ CH₂OH OH OH NH₂ CH₃ 1 5-27 CH₃ CH₂OHOH OH NH₂ F 1 5-28 CH₃ CH₂OH OH H NH₂ CH₂OH 1 5-29 CH₃ CH₂OH OH CH₂F NH₂CH₂OH 1 5-30 CH₃ CH₂OH OH CH₃ NH₂ CH₂OH 1 5-31 CH₃ CH₂OH OH F NH₂ CH₂OH1 5-32 CH₃ CH₂OH OH OH H CH₂OH 1 5-33 CH₂CH₃ CH₂OH OH OH NH₂ CH₂OH 15-34 CH₂CH₃ CH₂OH OH CH₂OH NH₂ CH₂OH 1 5-35 ^(n)Pr CH₂OH OH OH NH₂ CH₂OH1 5-36 ^(i)Pr CH₂OH OH OH NH₂ CH₂OH 1 5-37 ^(n)Bu CH₂OH OH OH NH₂ CH₂OH1 5-38 ^(i)Bu CH₂OH OH OH NH₂ CH₂OH 1 5-39 ^(t)Bu CH₂OH OH OH NH₂ CH₂OH1 5-40 ^(n)Pn CH₂OH OH OH NH₂ CH₂OH 1 5-41 ^(n)Hex CH₂OH OH OH NH₂ CH₂OH1 5-42 CH₂OH CH₂OH OH OH NH₂ CH₂OH 1 5-43 CH₂OH CH₂F OH OH NH₂ CH₂OH 15-44 CH₂OH CH₂F OH CH₂OH NH₂ CH₂OH 1 5-45 CH₂OH CH₂OH OH CH₂OH NH₂ CH₂OH1 5-46 CH₂OH CH₂OH OH NH₂ H CH₂OH 1 5-47 CH₂OH CH₂F OH NH₂ H CH₂OH 15-48 CH₂OH CH₂OH OH NHCH(CH₂OH)₂ H CH₂OH 1 5-49 CH₂OH CH₂F OHNHCH(CH₂OH)₂ H CH₂OH 1 5-50 CH₂OH CH₂OH OH F NH₂ CH₂OH 1 5-51 CH₂OH CH₂FOH F NH₂ CH₂OH 1 5-52 CH₂OH CH₂OH OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-53 CH₂OHCH₂F OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-54 CH₂OCH₃ CH₂OH OH OH NH₂ CH₂OH 15-55 CH₂OCH₃ CH₂F OH OH NH₂ CH₂OH 1 5-56 CH₂OCH₃ CH₂OH OH CH₂OH NH₂CH₂OH 1 5-57 CH₂OCH₃ CH₂F OH CH₂OH NH₂ CH₂OH 1 5-58 CH₂OCH₃ CH₂OH OH NH₂H CH₂OH 1 5-59 CH₂OCH₃ CH₂F OH NH₂ H CH₂OH 1 5-60 CH₂OCH₃ CH₂OH OHNHCH(CH₂OH)₂ H CH₂OH 1 5-61 CH₂OCH₃ CH₂F OH NHCH(CH₂OH)₂ H CH₂OH 1 5-62CH₂OCH₃ CH₂OH OH F NH₂ CH₂OH 1 5-63 CH₂OCH₃ CH₂F OH F NH₂ CH₂OH 1 5-64CH₂OCH₃ CH₂OH OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-65 CH₂OCH₃ CH₂F OH OHNHCH(CH₂OH)₂ CH₂OH 1 5-66 CH₂F CH₂OH OH OH NH₂ CH₂OH 1 5-67 CH₂F CH₂F OHOH NH₂ CH₂OH 1 5-68 CH₂F CH₂OH OH CH₂OH NH₂ CH₂OH 1 5-69 CH₂F CH₂F OHCH₂OH NH₂ CH₂OH 1 5-70 CH₂F CH₂OH OH NH₂ H CH₂OH 1 5-71 CH₂F CH₂F OH NH₂H CH₂OH 1 5-72 CH₂F CH₂OH OH NHCH(CH₂OH)₂ H CH₂OH 1 5-73 CH₂F CH₂F OHNHCH(CH₂OH)₂ H CH₂OH 1 5-74 CH₂F CH₂OH OH F NH₂ CH₂OH 1 5-75 CH₂F CH₂FOH F NH₂ CH₂OH 1 5-76 CH₂F CH₂OH OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-77 CH₂FCH₂F OH OH NHCH(CH₂OH)₂ CH₂OH 1 5-78 CH₃ CH₂OH OH OH NH₂ CH₂OH 2 5-79CH₃ CH₂F OH OH NH₂ CH₂OH 2 5-80 CH₃ CH₂OH OH CH₂OH NH₂ CH₂OH 2 5-81 CH₃CH₂F OH CH₂OH NH₂ CH₂OH 2 5-82 CH₃ CH₂OH OH F NH₂ CH₂OH 2 5-83 CH₂OHCH₂OH OH OH NH₂ CH₂OH 2 5-84 CH₂OH CH₂F OH OH NH₂ CH₂OH 2 5-85 CH₂OHCH₂F OH CH₂OH NH₂ CH₂OH 2 5-86 CH₂F CH₂OH OH OH NH₂ CH₂OH 2 5-87 CH₂FCH₂F OH OH NH₂ CH₂OH 2 5-88 CH₂F CH₂OH OH CH₂OH NH₂ CH₂OH 2

In the above Tables, preferred compounds are 1-1, 1-115, 1-119, 1-155,1-280, 1-354, 1-547, 1-556, 1-557, 3-1, 5-1, 5-3, 5-9, 5-22 or 5-28,more preferred are (2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside,(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside,(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-β-D-glucopyranosyl-α-D-glucopyranoside,(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-fluoro-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside,(1R,2S,3R,4R,5R)-1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside,(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-methoxy-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside,(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside, theirpharmacologically acceptable salts and their pharmacologicallyacceptable esters.

A compound having the general formula (I) can be produced using, forexample, a known compound for the starting raw material according to theprocesses described below.

In the aforementioned formula and following description, A, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and n are the same as previouslydefined. However, in the case R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ orR¹¹ indicates a hydroxyl group or a group having a hydroxyl group, saidhydroxyl group may optionally be protected.

Process A:

Process B:

Process Ba:

Process Bb:

Process Bc:

Process C:

In the aforementioned steps and following description, X¹ to X²⁵, Y^(a1)to Y^(a5) and Y^(c1) to Y^(c3) are the same or different, and eachrepresents a hydrogen atom or hydroxyl group (said hydroxyl group mayoptionally be protected by a protecting group), Y^(b1) to Y^(b5) are thesame or different, and each represents a halogen atom, hydrogen atom orhydroxyl group (said hydroxyl group may optionally be protected by aprotecting group), P¹ represents a protecting group of an amino groupsuch as R⁶ or a C1-C6 alkoxycarbonyl group (preferably at-butoxycarbonyl group) or C7-C16 aralkyloxycarbonyl group (preferably abenzyloxycarbonyl group), P² and P³ are the same or different, and eachrepresents a protecting group of an amino group such as R⁷ or a C1-C6alkoxycarbonyl group (preferably a t-butoxycarbonyl group) or a C7-C16aralkyloxycarbonyl group (preferably a benzyloxycarbonyl group), and L¹,L², L³ and L⁴ represent a hydroxyl group (said hydroxyl group mayoptionally be protected by a protecting group or the hydrogen atom mayoptionally be substituted by a leaving group) or a leaving group.

There are no particular limitations on the protecting group used toprotect a hydroxyl group provided the group is typically used to protecta hydroxyl group, examples of which include “aliphatic acyl groups” suchas alkyl carbonyl groups, e.g. formyl, acetyl, propionyl, butyryl,isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl,nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,nonadecanoyl, eicosanoyl and heneicosanoyl groups, carboxylated alkylcarbonyl groups, e.g. succinoyl, glutaroyl and adipoyl groups, halogenolower alkyl carbonyl groups, e.g. chloroacetyl, dichloroacetyl,trichloroacetyl and trifluoroacetyl groups, lower alkoxy lower alkylcarbonyl groups, e.g. methoxyacetyl groups, and unsaturated alkylcarbonyl groups, e.g. (E)-2-methyl-2-butenoyl groups; “aromatic acylgroups” such as aryl carbonyl groups, e.g. benzoyl, α-naphthoyl andβ-naphthoyl groups, halogenoaryl carbonyl groups, e.g. 2-bromobenzoyland 4-chlorobenzoyl groups, lower alkylated aryl carbonyl groups, e.g.2,4,6-trimethylbenzoyl and 4-toluoyl groups, lower alkoxylated arylcarbonyl groups, e.g. 4-anisoyl groups, carboxylated aryl carbonylgroups, e.g. 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoylgroups, nitrated aryl carbonyl groups e.g. 4-nitrobenzoyl and2-nitrobenzoyl groups, lower alkoxycarbonylated aryl carbonyl groupse.g. 2-(methoxycarbonyl)benzoyl groups, and arylated aryl carbonylgroups, e.g. 4-phenylbenzoyl groups; “tetrahydropyranyl ortetrahydrothiopyranyl groups” such as tetrahydropyran-2-yl,3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl,tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups;“tetrahydrofuranyl or tetrahydrothiofuranyl groups” such astetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups; “silyl groups”such as tri-lower alkyl silyl groups, e.g. trimethylsilyl,triethylsilyl, isopropyl dimethylsilyl, t-butyl dimethylsilyl, methyldiisopropylsilyl, methyl di-t-butylsilyl and triisopropylsilyl groups,and tri-lower alkyl silyl groups substituted with 1 to 2 aryl groups,e.g. diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl andphenyldiisopropylsilyl groups; “alkoxymethyl groups” such as loweralkoxymethyl groups, e.g. methoxymethyl, 1,1-dimethyl-1-methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl andt-butoxymethyl groups, lower alkoxylated lower alkoxymethyl groups, e.g.2-methoxyethoxymethyl groups, and halogeno lower alkoxymethyl groups,e.g. 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups;“substituted ethyl groups” such as lower alkoxylated ethyl groups, e.g.1-ethoxyethyl and 1-(isopropoxy)ethyl groups and halogenated ethylgroups, e.g. 2,2,2-trichloroethyl groups; “aralkyl groups” such as loweralkyl groups substituted with 1 to 3 aryl groups, e.g. benzyl,α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl,α-naphthyldiphenylmethyl and 9-anthrylmethyl groups, and lower alkylgroups substituted with 1 to 3 aryl groups in which an aryl ring issubstituted with a lower alkyl, lower alkoxy, halogen or cyano group,e.g. 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl,4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl andpiperonyl groups; “alkoxycarbonyl groups” such as lower alkoxycarbonylgroups, e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl andisobutoxycarbonyl groups, and lower alkoxycarbonyl groups substitutedwith halogen or tri-lower alkylsilyl groups, e.g.2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups;“alkenyloxy carbonyl groups” such as vinyloxycarbonyl andallyloxycarbonyl groups; and, “aralkyloxy carbonyl groups” in which anaryl ring may or may not be substituted with 1 to 2 lower alkoxy ornitro groups, e.g. benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl groups. There are no particular limitations onreagents used to protect diols provided they are normally used toprotect diols, and preferable examples include aldehyde derivatives suchas benzaldehyde, ketone derivatives such as acetone, and dimethoxycompounds such as 2,2-dimethoxypropane and dimethoxybenzyl.

The process for producing Compound (I) of the present invention iscomprised of the following three steps.

(1) Step A is a step wherein the left side portion of Compound (I) inthe form of intermediate (iii) is produced.

(2) Step B is a step wherein the right side portion of Compound (I) inthe form of Intermediate (vii) is produced, and process a, b or c can beselected corresponding to the desired Compound (I).

(3) Step C is a step wherein Compound (I) of the present invention isproduced by condensing Intermediate (iii) obtained in Step A andIntermediate (vii) obtained in Step B.

The following provides an explanation of each step.

(Process A)

Raw material compound (i) can be produced by protecting and deprotectinga hydroxyl group of a known compound in accordance with known processes.In addition, protection and deprotection of a hydroxyl group can also becarried out in this step as necessary.

Protection and deprotection of a hydroxyl group can be carried incompliance with commonly known processes such as the process describedin “Protective Groups in Organic Synthesis” by Green-Watts(Wiley-Interscience, USA).

In addition, deprotection can also be carried out in the mannerdescribed below.

In the case of using a silyl group for the hydroxyl group deprotectinggroup, it can normally be removed by treating either with a compoundthat forms a fluorine anion such as tetrabutyl ammonium fluoride,hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride, oran organic acid, such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, oran inorganic acid such as hydrochloric acid.

Furthermore, in the case of removal by a fluorine anion, the reactionmay be promoted by adding an organic acid such as formic acid, aceticacid or propionic acid.

There are no particular limitations on the solvent used provided itdissolves the starting substance to a certain extent without inhibitingthe reaction, and preferable examples include ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; nitriles such as acetonitrile andisobutyronitrile; water; organic acids such as acetic acid and mixedsolvents thereof.

There are no particular limitations on the reaction temperature orreaction time, and the reaction is normally carried out at 0° C. to 100°C. (and preferably 10° C. to 30° C.) for 1 to 24 hours.

In the case the hydroxyl group protecting group is an aralkyl group oraralkyloxy carbonyl group, normally a process in which it is removed bycontacting with a reducing agent in a solvent (and preferably contactreduction at normal temperature in the presence of a catalyst) or aprocess in which it is removed using an oxidizing agent, is usedpreferably.

There are no particular limitations on the solvent used during removalby catalytic reduction provided it is not involved in the presentreaction, and preferable examples include alcohols such as methanol,ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuranand dioxane; aromatic hydrocarbons such as toluene, benzene and xylene;aliphatic hydrocarbons such as hexane and cyclohexane; esters such asethyl acetate and propyl acetate; amides such as formamide,dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone andhexamethylphosphorotriamide; fatty acids such as formic acid and aceticacid; water and mixed solvents thereof, while more preferable examplesinclude alcohols, fatty acids, mixed solvents of alcohols and ethers,mixed solvents of alcohols and water and mixed solvents of fatty acidsand water.

There are no particular limitations on the catalyst used provided it isnormally used in catalytic reduction reactions, and preferable examplesof catalysts used include palladium carbon, palladium black, Raineynickel, platinum oxide, platinum black, rhodium-aluminium oxide,triphenylphosphine-rhodium chloride and palladium-barium sulfate.

There are no particular limitations on the pressure, and the reaction isnormally carried out at a pressure of 1 to 10 atmospheres.

Although reaction temperature and reaction time vary depending on thetypes of starting substance, solvent, catalyst and so forth, they arenormally 0° C. to 100° C. (and preferably 20° C. to 70° C.) and 5minutes to 48 hours (and preferably 1 hour to 24 hours).

There are no particular limitations on the solvent used during removalby oxidation provided it is not involved in the present reaction, andwater-containing organic solvents are preferable.

Preferable examples of such organic solvents include ketones such asacetone, halogenated hydrocarbons such as methylene chloride, chloroformand carbon tetrachloride, nitrites such as acetonitrile, ethers such asdiethyl ether, tetrahydrofuran and dioxane, amides such asdimethylformamide, dimethylacetamide and hexamethylphosphorotriamide,and sulfoxides such as dimethyl sulfoxide.

There are no particular limitations on the oxidizing agent used providedit is a compound normally used for oxidation, and potassium persulfate,sodium persulfate, cerium ammonium nitrate (CAN) or2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used preferably.

Although reaction temperature and reaction time vary depending on thetypes of starting substance, solvent, catalyst and so forth, they arenormally 0° C. to 150° C. and 10 minutes to 24 hours.

In addition, the protecting group can also be removed by allowing analkali metal such as lithium metal or sodium metal to act at −78° C. to−20° C. in liquid ammonia or an alcohol such as methanol or ethanol.

Moreover, it can also be removed by using an alkyl silyl halide such asaluminium chloride-sodium iodide or trimethylsilyl iodide in a solvent.

There are no particular limitations on the solvent used provided it isnot involved in the present reaction, and nitrites such as acetonitrile,halogenated hydrocarbons such as methylene chloride and chloroform, ormixed solvents thereof are used preferably.

Although reaction temperature and reaction time vary depending on thetypes of the starting substance, solvent and so forth, the reactiontemperature and reaction time are normally 0° C. to 50° C. and 5 minutesto 3 days.

Furthermore, in the case the reaction substrate has a sulfur atom,aluminium chloride-sodium iodide is used preferably.

In the case the hydroxyl group protecting group is an aliphatic acylgroup, aromatic acyl group or alkoxycarbonyl group, it is removed bytreating with base in a solvent.

There are no particular limitations on the base used provided it doesnot have an effect on the other parts of the compound, and examples ofbases that are used preferably include metal alkoxides such as sodiummethoxide; alkaline metal carbonates such as sodium carbonate, potassiumcarbonate and lithium carbonate; alkaline metal hydroxides such assodium hydroxide, potassium hydroxide, lithium hydroxide and bariumhydroxide; and ammonias such as aqueous ammonia and concentratedammonia-methanol.

There are no particular limitations on the solvent used provided it isnormally used in hydrolysis reactions, preferable examples of whichinclude water; organic solvents such as alcohols e.g. methanol, ethanoland n-propanol, and ethers e.g. tetrahydrofuran and dioxane; and mixedsolvents of water and the aforementioned organic solvents.

Although there are no particular limitations on the reaction temperatureand reaction time, and they vary according to the starting substance,solvent, base used and so forth, the reaction is normally carried out at0° C. to 150° C. for 1 hour to 10 hours to suppress side reactions.

In the case the hydroxyl group protecting group is an alkoxy methylgroup, tetrahydropyranyl group, tetrahydrothiopyranyl group,tetrahydrofuranyl group, tetrahydrothiofuranyl group or substitutedethyl group, the protecting group is normally removed by treating withacid in a solvent.

There are no particular limitations on the acid used provided it isnormally used as a Bronsted acid or Lewis acid, and although preferableexamples include Bronsted acids such as hydrogen chloride; inorganicacids e.g. hydrochloric acid, sulfuric acid and nitric acid; and,organic acids e.g. acetic acid, trifluoroacetic acid, methane sulfonicacid and p-toluene sulfonic acid; as well as Lewis acids such as borontrifluoride, a strongly acidic cation exchange resin such as Dowex 50Wcan also be used.

There are no particular limitations on the solvent used provided itdissolves the starting substance to a certain extent without inhibitingthe reaction, and preferable examples include aliphatic hydrocarbonssuch as hexane, heptane, ligroin and petroleum ether; aromatichydrocarbons such as benzene, toluene and xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esterssuch as ethyl formate, ethyl acetate, propyl acetate, butyl acetate anddiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethylether; alcohols such as methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol,glycerin, octanol, cyclohexanol and methyl cellusorb; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone andcyclohexanone; water and mixed solvents thereof, while more preferableexamples include halogenated hydrocarbons, esters and ethers.

Although reaction temperature and reaction time vary depending on thetypes, concentrations and so forth of the starting substance, solventand acid used, they are normally −10° C. to 100° C. (and preferably −5°C. to 50° C.) and 5 minutes to 48 hours (and preferably 30 minutes to 10hours).

In the case the hydroxyl group protecting group is an alkenyloxycarbonyl group, removal is normally achieved by treating with base undersimilar conditions as the removal reaction in the case the hydroxylgroup protecting group is an aforementioned aliphatic acyl group,aromatic acyl group or alkoxycarbonyl group.

Furthermore, in the case of an allyloxycarbonyl group, a process inwhich it is removed using palladium in particular as well astriphenylphosphine or bis(methyldiphenylphosphine) (1,5-cyclooctadiene)iridium (I).hexafluorophosphate is simple and can be carried out withfew side reactions.

In the case the hydroxyl group protecting group is a formyl group, it isremoved by treating with base in a solvent.

There are no particular limitations on the base used provided it doesnot have an effect on other parts of the compounds, and an alkalinemetal hydrogen carbonate such as potassium hydrogen carbonate is usedpreferably.

There are no particular limitations on the solvent used provided isnormally used in hydrolysis reactions, and preferable examples includewater; organic solvents such as alcohols e.g. methanol, ethanol andn-propanol, or ethers e.g. tetrahydrofuran and dioxane; and, mixedsolvents of water and the aforementioned organic solvents.

Although reaction temperature and reaction time vary depending on thetypes of the starting substance, solvent and base used and there are noparticular limitations on them, the reaction is normally carried out at0° C. to 150° C. for 1 hour to 10 hours to suppress side reactions.

In the case the hydroxyl group protecting group is a halogen-substitutedacetamide group such as a trifluoroacetamide group, it is removed bytreating with base in a solvent.

There are no particular limitations on the base used provided it doesnot have an effect on other parts of the compound, and a basic resinsuch as Dowex 1×4 (OH⁻) is used preferably.

There are no particular limitations on the solvent used provided it isnormally used in hydrolysis reactions, and preferable examples includewater; and, alcohols such as methanol, ethanol and n-propanol, withwater being more preferable.

A deprotecting group of an allyl group at the anomer position ispreferably a palladium catalyst such as palladium chloride or an iridiumcatalyst.

There are no particular limitations on the solvent used provided it isnormally used in catalytic reactions, and preferable examples includealcohol-based solvents such as methanol, ether-based solvents such astetrahydrofuran, and water, with methanol and tetrahydrofuran being morepreferable.

(Step A1)

This step is a step in which compound (ii) is produced, and is achievedby introducing a leaving group to a hydroxyl group at a desired locationas necessary, followed by carrying out a nucleophilic substitutionreaction with a reagent corresponding to the R¹ and R² groupsintroduced.

In the case the leaving group is a halogen atom, there are no particularlimitations on the solvent used provided it dissolves the startingsubstance without inhibiting the reaction, with preferable examplesincluding ethers such as diethyl ether, tetrahydrofuran and dioxane,amides such as dimethylformamide, dimethylacetamide andhexamethylphosphotriamide, halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane, nitriles such asacetonitrile and propionitrile, esters such as ethyl formate and ethylacetate and mixed solvents thereof, more preferable examples beinghalogenated hydrocarbons and ethers, and particularly preferableexamples being dichloromethane and tetrahydrofuran.

There are no particular limitations on the halogenation agent usedprovided it is normally used in reactions between hydroxyl groups andhalogen atoms, examples of which include dialkylaminosulfatrihalidessuch as diethylaminosulfatrifluoride (DAST), thionyl halides such asthionyl chloride, thionyl bromide and thionyl iodide, sulfuryl halidessuch as sulfuryl chloride, sulfuryl bromide and sulfuryl iodide,phosphorus trihalides such as phosphorus trichloride, phosphorustribromide and phosphorus triiodide, phosphorus pentahalides such asphosphorus pentachloride, phosphorus pentabromide and phosphoruspentaiodide, and phosphorus oxyhalides such as phosphorus oxychloride,phosphorus oxybromide and phosphorus oxyiodide.

The reaction temperature is 0° C. to the heating temperature (boilingpoint of the solvent used), and preferably room temperature to theheating temperature (boiling point of the solvent used).

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

In the case the leaving group is a sulfonyl group, there are noparticular limitations on the sulfonylation agent used provided it isnormally used in hydroxyl group sulfonylation reactions, examples ofwhich include alkane sulfonyl halides such as ethane sulfonyl chloride,aryl sulfonyl halides such as p-toluene sulfonyl chloride, and sulfonicacid anhydrides such as methane sulfonic acid anhydride, benzenesulfonic acid anhydride and trifluoromethane sulfonic acid anhydride.Preferable examples include methanesulfonyl chloride, p-toluenesulfonylchloride and trifluoromethanesulfonic acid anhydride.

There are no particular limitations on the solvent used provided itdissolves the starting substance to a certain extent without inhibitingthe reaction, examples of which include aliphatic hydrocarbons such ashexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons suchas benzene, toluene and xylene; halogenated hydrocarbons such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate and diethyl carbonate; and,ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane and diethylene glycol dimethyl ether.Preferable examples include halogenated hydrocarbons, esters and ethers,with tetrahydrofuran being more preferable.

There are no particular limitations on the base used provided it is usedas a base in normal reactions, preferable examples of which includeorganic bases such as triethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine,4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino) pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazbicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with triethylamine andpyridine being more preferable.

The reaction temperature is 0° C. to the heating temperature (boilingpoint of the solvent used), and preferably 0° C. to room temperature.

The reaction time is 10 minutes to 24 hours, and preferably 10 minutesto 1 hour.

Examples of the reagent used for the reagent corresponding to groups R¹and R² include commercially available reducing agents and halogenationagents.

Preferable examples of the reducing agent used include alkaline metalborohydrides such as sodium borohydride and lithium borohydride,hydrogenated aluminium compounds such as lithium aluminium hydride andaluminium triethoxide lithium hydride, and hydride reagents such assodium tellurium hydride.

There are no particular limitations on the solvent used provided itdissolves the starting substance without inhibiting the reaction, andpreferable examples include alcohols such as methanol and ethanol,ethers such as ether and tetrahydrofuran, and mixed solvents thereof.

There are no particular limitations on the halogenation agent usedprovided it is normally used in halogenation reactions, and preferableexamples include dialkylaminosulfatrihalides such asdiethylaminosulfatrifluoride (DAST), thionyl halides such as thionylchloride, thionyl bromide and thionyl iodide, sulfuryl halides such assulfuryl chloride, sulfuryl bromide and sulfuryl iodide, phosphorustrihalides such as phosphorus trichloride, phosphorus tribromide andphosphorus triiodide, phosphorus pentahalides such as phosphoruspentachloride, phosphorus pentabromide and phosphorous pentaiodide, andphosphorous oxyhalides such as phosphorous oxychloride, phosphorousoxybromide and phosphorous oxyiodide, with diethylaminosulfatrifluoridebeing more preferable.

There are no particular limitations on the solvent used provided itdissolves the starting substance to a certain extent without inhibitingthe reaction, and examples include ethers such as ether andtetrahydrofuran, with tetrahydrofuran being preferable.

The reaction temperature is 0° C. to the heating temperature (boilingpoint of the solvent used), and preferably room temperature to theheating temperature (boiling point of the solvent used).

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Step A2)

This step is a step in which intermediate (iii) is produced, and isachieved by introducing a leaving group at position 1 of compound (ii)following the process of step A1.

(Step B)

(Process Ba)

Raw material compound (iv) can be produced following the processdescribed in Tetrahedron, Vol. 26, 1985, p. 1469. Moreover, raw materialcompound (v) can be produced by protecting and deprotecting a hydroxylgroup of a known compound according to a known process. In addition,hydroxyl group protection and deprotection can also be carried out asnecessary in the present step in the same manner as Process A. Moreover,in the case of having a halogen atom for a substituent, a halogen atomcan be introduced according to the halogenation reaction of step A1.

(Step Ba1)

This step is a step in which a bicyclic compound (v) is produced, and isachieved by reducing the azide group of compound (iv) followed byheating.

There are no particular limitations on the solvent used provided itdissolves the starting substance, and examples include water-solubleethers such as tetrahydrofuran and dioxane, water, and mixed solventsthereof, with a mixed solvent of water and tetrahydrofuran beingpreferable.

Examples of azide group reducing agents include phosphines and aqueousammonia. Although examples include trialkyl phosphines such as trimethylphosphine and triethyl phosphine and aqueous ammonia, and triarylphosphines such as triphenyl phosphine and aqueous ammonia, a triarylphosphine such as triphenyl phosphine and aqueous ammonia arepreferable.

In addition, a catalyst can also be used for the reducing agent. Thereare no particular limitations on the catalyst used provided it isnormally used in catalytic reduction reactions, and examples includepalladium carbonate, palladium black, palladium carbon, palladiumhydroxide, Rainey nickel, platinum oxide, platinum black,rhodium-aluminium hydroxide, triphenyl phosphine-rhodium chloride andpalladium-barium sulfate, with palladium carbon and palladium hydroxidebeing preferable.

In the case of using a catalyst for the reducing agent, there are noparticular limitations on the solvent used provided it dissolves thestarting substance without inhibiting the reaction, and preferableexamples include alcohols such as methanol and ethanol, ethers such astetrahydrofuran and dioxane, fatty acids such as acetic acid, and esterssuch as ethyl acetate, with methanol being more preferable.

The reaction temperature is 0° C. to 50° C., and preferably 0° C. toroom temperature.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Step Ba2)

This step is a step in which compound (vi) having a protected aminogroup is produced, and is achieved by protecting the amino group ofcompound (v) with a suitable protecting group.

There are no particular limitations on the solvent used provided itdissolves the starting substance without inhibiting the reaction, andpreferable examples include ethers such as tetrahydrofuran, dioxane,dimethoxyethane and diethylene glycol, alcohols such as methanol andethanol, ketones such as acetone and methyl ethyl ketone, amides such asN,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such asdimethyl sulfoxide.

There are no particular limitations on the reagent used provided it isnormally used in reactions in which a protecting group is introduced toa free amino group, and preferable examples include di-t-butyldicarbonate, benzyloxycarbonyl chloride and p-nitrobenzyloxycarbonylchloride, with di-t-butyl carbonate being more preferable.

There are no particular limitations on the base used provided it is usedas a base in normal reactions, and preferable examples include alkalineearth carbonates, alkaline earth hydrogen carbonates and organic bases,with alkaline metal hydrogen carbonates being more preferable.

The reaction temperature is 0° C. to 50° C., and preferably 0° C. toroom temperature.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 10hours.

(Step Ba3)

This step is a step in which pyrrolidine compound (viia) is produced,and is achieved by opening one of the rings of bicyclic compound (vi),protecting the hydroxyl group as necessary, and deprotecting thehydroxyl group at the site that glycosylates with intermediate (iii).

There are no particular limitations on the reducing agent used providedit is normally used in reduction reactions, and examples include alkalimetal borohydrides such as sodium borohydride and lithium borohydride,hydrogenated aluminium compounds such as lithium aluminium hydride andaluminium triethoxide lithium hydride, and hydride reagents such assodium tellurium hydride, with sodium borohydride being preferable.

There are no particular limitations on the solvent used provided itdissolves the starting substance to a certain extent without inhibitingthe reaction, and examples include alcohols such as methanol andethanol, ethers such as dioxane, ether and tetrahydrofuran, water andmixed solvents thereof, with methanol or tetrahydrofuran beingpreferable.

The reaction temperature is 0° C. to the boiling point of the solventused, and preferably 50° C. to the boiling point of the solvent used.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Process Bb)

Raw material compound (viii) can be produced according to the processdescribed in Carbohydrate Research, Vol. 169, 1987, p. 23. Moreover, rawmaterial compound (viii) can be produced by protecting and deprotectinga hydroxyl group of a known compound according to a known process. Inaddition, the hydroxyl group can also be protected and deprotected asnecessary in the present step in the same manner as Process A. Moreover,in the case of having a halogen atom for a substituent, a halogen atomcan be introduced according to the halogenation reaction of step A1.

(Step Bb1)

The present step is a step in which compound (ix) is produced, and isachieved by introducing a leaving group at the 6-position of rawmaterial compound (viii) under the same conditions as step A1. Inaddition, the leaving group can be further converted to a differentleaving group as necessary.

(Step Bb2)

The present step is a step in which compound (x) having an olefinterminal is produced, and is achieved by heating compound (ix) in asolvent in the presence of a catalyst.

There are no particular limitations on the solvent used provided itdissolves the starting substance without inhibiting the reaction, andpreferable examples include alcohols such as methanol, ethanol andisopropanol, water, and mixed solvents thereof, with a mixed solvent ofwater and isopropanol being more preferable.

There are no particular limitations on the catalyst used provided it isnormally used in reactions in which a double bond is reduced, andexamples include zinc, palladium carbon, platinum, Rainey nickel, alkalimetal borohydrides such as sodium borohydride and lithium borohydride,hydrogenated aluminium compounds such as such as lithium aluminiumhydride and aluminium triethoxide lithium hydride, and hydride reagentssuch as sodium tellurium hydride, with zinc being preferable.

The reaction temperature is 0° C. to the boiling point of the solventused, and preferably 50° C. to the boiling point of the solvent used.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Step Bb3)

The present step is a step in which compound (xi) having a hydroxylaminogroup is produced, and is achieved by treating compound (x) with ahydroxylamine hydrochloride.

There are no particular limitations on the solvent used provided itdissolves the starting substance without inhibiting the reaction, andpreferable examples include mixed solvents of alcohols such as methanol,ethanol and isopropanol, and organic bases such as pyridine, with amixed solvent of ethanol and pyridine being particularly preferable.

The reaction temperature is 0° C. to the boiling point of the solventused, and preferably 0° C. to 60° C.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Step Bb4)

The present step is a step in which bicyclic compound (xii) is produced,and is achieved by cyclizing compound (xi) by heating in a solvent.

There are no particular limitations on the solvent used provided it isinactive, and preferable examples include aromatic hydrocarbons such asbenzene, toluene and xylene, with toluene being particularly preferable.

The reaction temperature is 0° C. to the boiling point of the solventused, and preferably 50° C. to the boiling point of the solvent used.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

(Step Bb5)

The present step is a step in which intermediate compound (viib) isproduced, and is achieved by deprotecting the hydroxyl group at the sitethat glycosylates with intermediate (iii), and protecting the secondaryamine of compound (xii) under similar conditions to step A1.

(Process Bc)

Raw material compound (xiii) can be produced according to the processdescribed in the Chemical Pharmaceutical Bulletin, Vol. 39, 1991, p.2807. Moreover, raw material compound (xiii) can be produced byprotecting and deprotecting the hydroxyl group of a known compoundaccording to a known process. In addition, protection and deprotectionof the hydroxyl group can also be carried out as necessary in thepresent step in the same manner as Process A. Moreover, in the case ofhaving a halogen atom for a substituent, a halogen atom can beintroduced according to the halogenation reaction of Step A1.

(Step Bc1)

The present step is a step in which intermediate compound (viic) isproduced, and is achieved by deprotecting the hydroxyl group protectinggroup of raw material compound (xiii).

(Process C)

(Step C1)

The present step is a step in which desired compound (I) is produced,and is achieved by carrying out a glycosylation reaction withintermediate compounds (iii) and (vii), and deprotecting the hydroxylgroup and amino group as necessary in accordance with establishedmethods.

Preferable examples of the deprotecting group at the anomer position ofcompound (iii) include fluorine, bromine, chlorine, trichloroimidate,diphenyl phosphate, diethyl phosphite, thiomethyl and phenylthio groups.

There are no particular limitations on the solvent used provided it isinactive, and preferable examples include halogenated hydrocarbons suchas methylene chloride and chloroform, ethers such as ether andtetrahydrofuran, and aromatic hydrocarbons such as benzene, toluene andxylene, with more preferable examples including halogenated hydrocarbonsand ethers, and particularly preferable examples including methylenechloride and ether.

There are no particular limitations on the catalyst used provided it isnormally used in glycosylation reactions, and preferable examplesinclude trimethylsilyl trifluoromethanesulfonic acid,trifluoromethanesulfonic acid, boron trifluoride ether complex,toluenesulfonic acid, silver trifluoromethanesulfonic acid andtetrabutyl ammonium iodide.

The reaction temperature is 0° C. to the boiling point of the solventused, and preferably room temperature.

The reaction time is 10 minutes to 24 hours, and preferably 1 hour to 5hours.

In addition, compound (I) can also be produced by deprotecting thehydroxyl group after the glycosylation reaction with intermediatecompounds (iii) and (viic), and then additionally subjecting to basicconditions.

In addition, in the case n=2, compound (I) can be produced using atrisaccharide derivative for the raw material compound in a processsimilar to processes A and C.

In addition, in the case of having a basic group, the desired compound(I) can be converted to an acid addition salt, preferably ahydrochloride, in accordance with ordinary methods.

Following completion of the reactions of each of the aforementionedsteps, the desired compound is collected from the reaction mixture inaccordance with ordinary methods. For example, the desired compound isobtained by suitably neutralizing the reaction mixture, or in the caseof the presence of insoluble matter, removing the insoluble matter byfiltration, followed by adding water and an immiscible organic solventsuch as ethyl acetate, washing with water and so forth, and thenseparating the organic phase containing the desired compound, dryingwith anhydrous magnesium sulfate, for example, and finally distillingoff the solvent.

The resulting desired compound can be separated and purified asnecessary by suitably combining ordinary methods such asrecystallization, reprecipitation or other methods normally routinelyused for the separation and purification of organic compounds, examplesof which include adsorption column chromatography, distribution columnchromatography and other methods using a synthetic adsorbent, methodsusing ion exchange chromatography, and forward and/or reverse phasechromatography using silica gel or alkylated silica gel, followed byeluting with a suitable eluent.

Oligosaccharide derivatives of the present invention having theaforementioned general formulas (I), (Ia) and (Ib), theirpharmacologically acceptable salts and their pharmacologicallyacceptable esters are administered in various forms. There are noparticular limitations on the administration form, and each type ofpreparation form is determined according to the formulation, the age,gender and other conditions of the patient, the degree of the diseaseand so forth. Examples of formulations in the case of oraladministration include tablets, pills, powders, granules, syrups,liquids, suspensions, emulsions, granules and capsules. Administrationis performed intrarectally in the case of suppositories. Administrationis preferably performed orally.

Each of these formulations can be formulated in accordance with ordinarymethods using known adjuvants that can normally be used in knownpharmaceutical fields, examples of which include vehicles, binders,disintegration agents, lubricants, dissolving agents, correctives andcoating agents.

When forming into the form of tablets, a wide range of carriersconventionally known in this field can be used for the carrier, examplesof which include vehicles such as lactose, sucrose, sodium chloride,glucose, urea, starch, calcium carbonate, kaolin, crystalline celluloseand silicic acid, binders such as water, ethanol, propanol, simplesyrup, liquid glucose, liquid starch, liquid gelatin, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegration agents such as dry starch, sodium alginate,powdered agar, powdered laminarin, sodium bicarbonate, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, monoglyceride stearate, starch and lactose, disintegrationinhibitors such as sucrose, stearine, cocoa butter and hydrogenatedoils, absorption promoters such as quaternary ammonium salts and sodiumlauryl sulfate, moisturizers such as glycerin and starch, adsorbentssuch as starch, lactose, kaolin, bentonite and colloidal silicic acid,and lubricants such as refined talc, stearates, powdered boric acid andpolyethylene glycol. Moreover, tablets can be tablets provided with anordinary coating as necessary, examples of which include sugar-coatedtablets, gelatin-sealed tablets, enteric coated tablets and film-coatedtablets, tablets provided with two layers of coatings or multilayertablets.

When forming into the form of pills, a wide range of carriersconventionally known in this field can be used for the carrier, examplesof which include vehicles such as glucose, lactose, starch, cocoabutter, hardened vegetable oils, kaolin and talc, binders such aspowdered gum Arabic, powdered tragacanth, gelatin and ethanol, anddisintegration agents such as laminaran agar.

When forming into the form of suppositories, a wide range of carriersconventionally known in this field can be used for the carrier, examplesof which include polyethylene glycol, cocoa butter, higher alcohols,esters of higher alcohols, gelatin and semi-synthetic glycerides.

Moreover, other pharmaceuticals such as colorants, preservatives,fragrances, flavorings and sweeteners may also be included as necessary.

Although there are no particular limitations on the amount of activeingredient compound contained in the aforementioned pharmaceuticalpreparations, and it can be suitably selected over a wide range, it issuitable to normally contain an amount of 1 to 70% by weight, andpreferably 1 to 30% by weight, in the total composition.

Although varying according to symptoms, age, body weight, administrationmethod, drug form and so forth, the normal daily adult dosage has alower limit of 0.001 mg (preferably 0.01 mg and more preferably 0.1 mg),and an upper limit of 2,000 mg (preferably 200 mg and more preferably100 mg), and this dosage can be administered in a single administrationor in multiple administrations.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is explained in more detail by way ofExamples, Reference examples, Test examples and Preparation examples,but the present invention is not limited thereto.

Example 1 (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-1)

(1a) Allyl4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-2,3,6-tri-O-acetyl-D-glucopyranoside

D-Maltose monohydrate (36.0 g, 100 mmol) was dissolved in pyridine (200mL) and acetic anhydride (100 mL) and 4-dimethylaminopyridine (0.6 g,4.90 mol) were added thereto, followed by stirring of the mixture atroom temperature for 12 hours. The reaction mixture was ice-cooled andice (30 g) was added thereto, followed by stirring of the mixture for 30minutes. The reaction mixture was extracted with ethyl acetate (500 mL)and the organic layer was washed with diluted hydrochloric acid (1N, 200mL), saturated aqueous sodium hydrogencarbonate (100 mL) and saturatedbrine (100 mL). After it was dried with anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The residue wasdissolved in methylene chloride (700 mL) and allyl alcohol (34 mL, 500mol) and trimethylsilyl trifluoromethanesulfonate (18.1 mL, 100 mmol)were added thereto, followed by stirring of the mixture at roomtemperature for 2 hours. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate (1 L) and after it was extracted withmethylene chloride (500 mL), the organic layer was washed with saturatedbrine (300 mL) and dried with anhydrous sodium sulfate, followed bydistilling off of the solvent under reduced pressure. The residue waspurified using silica gel flash column chromatography (ethylacetate:hexane, 2:3, V/V) to obtain the desired title compound (30.0 g,yield 31%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.99 (3H, s), 2.00 (3H, s), 2.01 (6H, s),2.03 (3H, s), 2.09 (3H, s), 2.14 (3H, s), 3.65-3.69 (1H, m), 3.93-4.14(4H, m), 4.20-4.26 (2H, m), 4.30 (1H, dd, J=13.2, 5.1 Hz), 4.47 (1H, dd,J=12.4, 2.9 Hz), 4.57 (1H, d, J=8.1 Hz), 4.83-4.87 (2H, m), 5.04 (1H, t,J=9.5 Hz), 5.18-5.28 (3H, m), 5.35 (1H, t, J=9.5 Hz), 5.41 (1H, d, J=3.7Hz), 5.79-5.88 (1H, m);

MS (FAB) m/z: 677 (M+H)⁺, 699 (M+Na)⁺.

(1b) Allyl 4-O-(4,6-O-benzylidene-α-D-glucopyranosyl)-D-glucopyranoside

The compound (17.0 g, 25.1 mmol) synthesized in Example 1 (1a) wasdissolved in methanol (250 mL) and sodium methoxide (2 mL, 9.8 mol) wasadded thereto under ice-cooling, followed by stirring of the mixture atroom temperature for 1 hour. After Dowex 50w×8 was added to the mixtureuntil the reaction mixture became neutral and was filtered, the solventwas distilled off under reduced pressure. The residue was dissolved inN,N-dimethylformamide (200 mL) and benzaldehyde dimethylacetal (4.65 mL,31.0 mmol) and p-toluenesulfonic acid monohydrate (226 mg, 1.19 mmol)were added thereto, followed by stirring of the mixture at 20 mmHg and50° C. for 5 hours. After triethylamine (1 mL) was added to the reactionmixture, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography (ethylacetate:hexane:methanol, 5:5:1, V/V/V) to obtain the desired titlecompound (10.0 g, yield 85%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CD₃OD): δ 3.16 (1H, t, J=9.5 Hz), 3.28-3.32 (1H, m),3.35 (1H, t, J=9.5 Hz), 3.42 (1H, t, J=9.5 Hz), 3.47 (1H, dd, J=9.5, 3.6Hz), 3.54 (1H, t, J=9.5 Hz), 3.61-3.66 (2H, m), 3.71 (1H, t, J=9.5 Hz),3.74-3.81 (2H, m), 4.02-4.07 (1H, m), 4.12 (1H, dd, J=10.3, 5.1 Hz),4.22-4.29 (2H, m), 5.06 (1H, d, J=10.2 Hz), 5.10 (1H, d, J=4.4 Hz), 5.23(1H, d, J=17.5 Hz), 5.81-5.91 (1H, m), 7.22-7.24 (3H, m), 7.38-7.40 (2H,m);

MS (FAB) m/z: 471 (M+H)⁺, 493 (M+Na)⁺.

(1c) Allyl4-O-(4,6-O-benzylidene-2,3-di-O-benzyl-αD-glucopyranosyl)-2,3,6-tri-O-benzyl-D-glucopyranoside

The compound (10.0 g, 21.3 mmol) synthesized in Example 1 (1b) wasdissolved in N,N-dimethylformamide (300 mL) and sodium hydride (9.28 g,213 mmol) was added thereto under ice-cooling, followed by stirring ofthe mixture under ice-cooling for 30 minutes. After benzyl bromide (25mL, 213 mmol) was added thereto and the mixture was stirred at roomtemperature for 3 hours, water (100 mL) was added to the reactionmixture and the mixture was extracted with ethyl acetate (500 mL). Theextract was washed with water (100 mL) and saturated brine (100 mL) anddried with anhydrous sodium sulfate, followed by distilling off of thesolvent under reduced pressure. The residue was purified using silicagel flash column chromatography (hexane:ethyl acetate, 9:1, V/V) toobtain the desired title compound (18.5 g, yield 94%) as a pale yellowsolid.

¹H NMR (400 MHz, CDCl₃): δ 3.49-3.68 (4H, m), 3.76-3.90 (3H, m),3.93-4.03 (2H, m), 4.09-4.19 (3H, m), 4.42-4.78 (10H, m), 4.84-5.07 (3H,m), 5.23 (1H, t, J=9.8 Hz), 5.35 (1H, dd, J=17.5, 8.8 Hz), 5.54 (1H, d,J=3.9 Hz), 5.74 (1H, dd, J=24.5, 3.9 Hz), 5.92-6.02 (1H, m), 7.17-7.51(5H, m);

MS (FAB) m/z: 922 (M+H)⁺, 944 (M+Na)⁺.

(1d) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-α-D-glucopyranosyl)-D-glucopyranoside

The compound (30.0 g, 32.5 mmol) synthesized in Example 1 (1c) wasdissolved in diethyl ether (300 mL) and methylene chloride (150 mL) andlithium aluminium hydride (1.85 g, 48.8 mmol) and aluminium chloride(III) (6.93 g, 52.0 mmol) were added thereto, followed by heating of themixture under reflux for 2 hours. After the reaction mixture was dilutedwith diethyl ether (500 mL), 1N aqueous sodium hydroxide solution (5.6mL) was added to the reaction mixture, followed by stirring of themixture for 1 hour. After it was extracted with ethyl acetate, theorganic layer was washed with 10% aqueous hydrochloric acid solution(100 mL), saturated aqueous sodium hydrogencarbonate solution (150 mL)and saturated brine (100 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 4:1-3:1-2:1, V/V) to obtain the desired titlecompound (21.1 g, yield 71%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.40-3.71 (6H, m), 3.74-3.85 (2H, m) 3.90(2H, m), 3.99-4.07 (1H, m), 4.10-4.20 (3H, m), 4.42-4.70 (7H, m),4.76-5.08 (6H, m), 5.23 (1H, t, J=10.7 Hz), 5.35 (1H, dd, J=18.6, 8.8Hz), 5.64 (1H, dd, J=13.7, 3.9 Hz), 5.93-6.02 (1H, m), 7.18-7.34 (30H,m);

MS (FAB) m/z: 946 (M+Na)⁺, 924 (M+H)⁺.

(1e) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-D-glucopyranoside

The compound (15.2 g, 16.5 mmol) synthesized in Example 1 (1d) wasdissolved in pyridine (300 mL) and p-toluenesulfonyl chloride (12.5 g,66.0 mmol) and 4-dimethylaminopyridine (2.01 g, 16.4 mmol) were addedthereto, followed by stirring of the mixture at room temperature for 13hours. After the solvent was distilled off under reduced pressure, theresidue was poured into 10% aqueous hydrochloric acid solution (50 mL)and ethyl acetate (200 mL). The organic layer was washed with 10%aqueous hydrochloric acid solution (50 mL), saturated aqueous sodiumhydrogencarbonate solution (20 mL) and saturated brine (20 mL) and driedwith anhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtaintosylate (13.5 g, yield 76%) as a yellow oil. The tosylate (13.5 g, 12.5mol) was dissolved in diethyl ether (300 mL) and lithium aluminiumhydride (950 mg, 25 mol) was added to the reaction mixture, followed byheating of the mixture under reflux for 1 hour. 1N aqueous NaOH solution(1.0 mL) and water (1.0 mL) were added thereto and the mixture wasstirred for 30 minutes. After celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 6:1, V/V)to obtain the desired title compound (10.2 g, yield 90%) as a colorlesssolid.

¹H NMR (400 MHz, CDCl₃): δ 1.08 (3H, d, J=5.8 Hz), 3.01 (1H, t, J=9.5Hz), 3.35 (1H, dd, J=9.5, 3.7 Hz), 3.44-3.50 (2H, m), 3.66-3.72 (5H, m),3.78 (1H, t, J=9.5 Hz), 3.93 (1H, t, J=9.5 Hz), 4.07 (1H, dd, J=12.8,5.9 Hz), 4.35 (1H, dd, J=13.1, 5.1 Hz), 4.39-4.57 (7H, m), 4.69 (2H, d,J=11.7 Hz), 4.77-4.88 (3H, m), 5.13 (1H, d, J=10.0 Hz), 5.26 (1H, d,J=16.9 Hz), 5.47 (1H, d, J=3.7 Hz), 5.84-5.92 (1H, m), 7.09-7.26 (30H,m);

MS (FAB) m/z: 907 (M+H)⁺.

(1f)4-O-(6-Deoxy-2,3,4-tri-O-benzyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-D-glucopyranoside

The compound (10.2 g, 11.2 mmol) synthesized in Example 1 (1e) wasdissolved in methanol (40 mL) and tetrahydrofuran (100 mL) and palladiumchloride (II) (400 mg, 2.24 mmol) was added thereto, followed bystirring of the mixture at room temperature for 14 hours. After thereaction mixture was subjected to celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 5:1-4:1,V/V) to obtain the desired title compound (8.17 g, yield 84%) as paleyellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.14 (3H, d, J=6.6 Hz), 3.09 (1H, t, J=9.5Hz), 3.41-3.47 (2H, m), 3.62-3.81 (4H, m), 3.96-4.05 (2H, m), 4.01-4.14(1H, m), 4.49-4.68 (6H, m), 4.74-4.78 (2H, m), 4.84-4.96 (4H, m), 5.22(1H, d, J=3.6 Hz), 5.51 (1H, d, J=3.7 Hz), 7.19-7.34 (30H, m);

MS (FAB) m/z: 889 (M+Na)⁺.

(1g) Methyl3-O-benzoyl-N-benzoyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside

Methyl N-benzoyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside(Tetrahedron, 1986, vol. 42, p. 5685-5692) (13.9 g, 49.8 mmol) wasdissolved in methylene chloride (200 mL) and pyridine (20 mL, 249.0mmol) and benzoyl chloride (11.6 mL, 99.6 mmol) were added thereto,followed by stirring of the mixture at room temperature for 2 hours.After 1N hydrochloric acid (200 mL) was added to the reaction mixture at0° C. and the mixture was extracted with methylene chloride (100 mL),the organic layer was washed with saturated aqueous sodiumhydrogencarbonate (200 mL) and saturated brine (200 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain thedesired title compound (15.82 g, yield 83%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.42-3.46 (4H, 3s), 3.60 (1H, dd, J=32.2,10.8 Hz), 4.54 (1H, d, J=34.2 Hz), 4.64 (1H, br, d, J=7.9 Hz), 4.85 (1H,d, J=36.2 Hz), 5.13-5.22 (2H, m), 5.47 (1H, s), 7.29-7.35 (5H, m),7.41-7.45 (2H, m), 7.59 (1H, t, J=7.8 Hz), 7.95 (2H, t, J=7.8 Hz);

MS (FAB) m/z: 406 (M+Na)⁺, 384 (M+H)⁺.

(1h) Benzyl(2R,3R,4R)-3-benzoyloxy-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

The compound (15.8 g, 41.3 mmol) synthesized in Example 1 (1g) wasdissolved in trifluoroacetic acid:water (4:1, 160 mL) and the mixturewas stirred at room temperature for 15 minutes. After water (200 mL) wasadded to the reaction mixture at 0° C. and the mixture was extractedwith methylene chloride (300 mL), the organic layer was washed withsaturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine(200 mL) and dried with anhydrous sodium sulfate, followed by distillingoff of the solvent under reduced pressure. The residue was dissolved inethanol (150 mL) and the compound obtained by dissolving sodiumborohydride (0.78 g, 20.7 mmol) in water (15 mL) was added thereto,followed by stirring of the mixture at 0° C. for 20 minutes. Aftersaturated aqueous ammonium chloride (20 mL) was added to the reactionmixture at 0° C., ethanol was distilled off under reduced pressure.After water (100 mL) was added thereto and the mixture was extractedwith ethyl acetate (100 mL), the organic layer was washed with saturatedbrine (100 mL) and dried with anhydrous sodium sulfate, followed bydistilling off of the solvent under reduced pressure. The residue waspurified using silica gel flash column chromatography (hexane:ethylacetate, 1:1, V/V) to obtain the desired title compound (14.2 g, yield89%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.68 (1H, d, J=11.7 Hz), 3.86 (1H, dd,J=11.7, 4.4 Hz), 3.93-4.04 (2H, m), 4.25-4.32 (2H, m), 5.09-5.32 (3H,m), 7.32-7.46 (7H, m), 7.59 (1H, t, J=7.4 Hz), 7.99 (2H, d, J=8.8 Hz);

MS (FAB) m/z: 372 (M+H)⁺.

(1i) Benzyl(2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-hydroxypyrrolidine-1-carboxylate

The compound (4.26 g, 11.5 mmol) synthesized in Example 1 (1 h) wasdissolved in dichloromethane:cyclohexane (1:2, 180 mL) and benzyltrichloroacetoimidate (10.6 mL, 57.5 mmol) and trifluoromethanesulfonicacid (0.15 mL, 1.7 mmol) were added thereto, followed by stirring of themixture at room temperature for 3 hours. After saturated aqueous sodiumhydrogencarbonate (10 mL) was added to the reaction mixture at 0° C. andthe mixture was diluted with ethyl acetate (200 mL), it was washed withwater (300 mL) and saturated brine (300 mL) and dried with anhydroussodium sulfate, followed by distilling of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 10:1-5:1, V/V) to obtain 7.85 g ofa pale yellow oil. Thus obtained 7.85 g of pale yellow oil was dissolvedin methanol (100 mL) and 1M aqueous potassium carbonate solution (4 mL)was added thereto, followed by stirring of the mixture at roomtemperature for 5 hours. After methanol was distilled off under reducedpressure, water (100 mL) was added thereto and the mixture was extractedwith ethyl acetate (100 mL) and then, the organic layer was washed withsaturated brine (100 mL). After it was dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatographyhexane:ethyl acetate, 2:1, V/V) to obtain the desired title compound(4.06 g, yield 64%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.35 (1H, dd, J=11.7, 3.7 Hz), 3.51-3.72 (1H,m), 3.66-3.89 (4H, m), 4.37-4.52 (5H, m), 4.98-5.07 (2H, m), 7.09-7.26(15H, m);

MS (FAB) m/z: 448 (M+H)⁺.

(1j) Benzyl(2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranosyl]oxy}pyrrolidine-1-carboxylateBenzyl(2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-β-D-glucopyranosyl]oxy}pyrrolidine-1-carboxylate

The compound (13.5 g, 15.57 mmol) synthesized in Example 1 (1f) wasdissolved in methylene chloride (250 mL) and trichloroacetonitrile (10mL, 134.3 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (13.0 g, 82%) as a yellow oil. The compound (5.48 g, 12.2mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (400mL) and imidate (13.0 g, 13.0 mmol) was added thereto. A solution oftrimethylsilyl trifluoromethanesulfonate (222 μL, 1.22 mmol) in diethylether (2 mL) was added thereto and the mixture was stirred at roomtemperature for 45 minutes. After triethylamine (1 mL) was added to thereaction mixture, the solvent was distilled off under reduced pressure.The residue was purified using silica gel flash column chromatography(hexane:diethyl ether, 4:1, V/V) to obtain the desired title compound αisomer (11.6 g, 56%) as a pale yellow oil and further the β isomer (3.7g, 18%) as a pale yellow oil.

α isomer: ¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H, d, J=5.9 Hz), 3.10-3.22(2H, m), 3.30-3.38 (2H, m), 3.42 (1H, t, J=8.8 Hz), 3.50-3.70 (5H, m),3.76-3.87 (5H, m), 4.01-4.10 (1H, m), 4.26-4.51 (9H, m), 4.61 (1H, d,J=11.0 Hz), 4.69-4.88 (8H, m), 4.96-5.16 (3H, m), 7.19-7.34 (43H, m),7.43 (2H, d, J=7.3 Hz);

MS (FAB) m/z: 1318 (M+Na)⁺.

β isomer: ¹H NMR (400 MHz, CDCl₃): δ 1.17 (3H, d, J=6.5 Hz), 3.10 (1H,t, J=9.1 Hz), 3.41-3.48 (3H, m), 3.54-3.63 (3H, m), 3.69-3.78 (4H, m),3.81-3.92 (2H, m), 4.02 (1H, s, J=8.79 Hz), 4.25 (1H, d, J=4.39 Hz),4.40-4.63 (13H, m), 4.73-4.79 (3H, m), 4.86-4.95 (4H, m), 5.09-5.19 (1H,m), 5.53 (1H, d, J=3.67 Hz), 7.18-7.30 (45H, m);

MS (FAB) m/z: 1296 (M+H)⁺.

(1k) (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (5.60 g, 4.32 mmol) synthesized in Example 1 (1j) wasdissolved in methanol (350 mL) and hydrochloric acid (4.8 mL) and 20%palladium hydroxide-carbon (2.8 g) were added thereto, followed bystirring of the mixture at room temperature under a hydrogen atmospherefor 4 hours. After celite filtration, 18% ammonia water (6 mL) was addedthereto and the solvent was distilled off under reduced pressure. Theresidue was purified by ion exchange resin (Dowex 50w×8) column(water—5% ammonia water). Further, it was purified using silica gelflash column chromatography (ethyl acetate:methanol:water, 2:2:1, V/V)to obtain the desired title compound (1.20 g, 63%) as a colorless solid.

[α]D20 +145.7 (c 0.36, H₂O);

¹H NMR (400 MHz, D₂O): δ 1.28 (3H, d, J=6.6 Hz), 2.93 (1H, dd, J=12.4,3.0 Hz), 3.12-3.20 (3H, m), 3.57-3.65 (4H, m), 3.71-3.87 (6H, m),3.92-3.98 (2H, m), 4.32-4.34 (1H, m), 5.13 (1H, d, J=3.6 Hz), 5.34 (1H,d, J=3.0 Hz);

¹³CNMR (125.70 MHz, D₂O): δ 16.72, 51.62, 60.64, 61.62, 64.84, 68.79,70.94, 71.07, 72.13, 72.83, 73.48, 74.96, 75.64, 77.13, 84.01, 97.44,99,88;

MS (FAB) m/z: 442 (M+H)⁺, 464 (M+Na)⁺.

Example 2 (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-1)

(2a) Allyl 4-O-β-D-glucopyranosyl-D-glucopyranoside

α-D-cellobiose octacetate (48.59 g, 71.6 mmol) was dissolved inmethylene chloride (600 mL), and allyl alcohol (29 mL, 0.43 mol) andtrimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were addedthereto under ice-cooling, followed by stirring of the mixture at roomtemperature for 1.5 hours. Water (200 mL) was added to the reactionmixture and the mixture was extracted with methylene chloride (200 mL).After the extract was washed with saturated brine (100 mL) and driedwith anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was dissolved in methanol (300 mL) andsodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling,followed by stirring of the mixture at room temperature for 2 hours.After Dowex 50w×8 was added thereto until the reaction mixture becameneutral and it was filtered, the solvent was distilled off under reducedpressure. The residue was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain thedesired title compound (24.8 g, yield 91%) as pale yellow amorphousmatter.

¹H NMR (400 MHz, CDCl₃): δ 3.20-3.40 (9H, m), 3.40-3.65 (4H, m),4.00-4.40 (3H, m), 5.18 (1H, d, J=11.7 Hz), 5.35 (1H, d, J=17.6 Hz),5.95 (1H, ddd, J=17.6, 11.7, 5.9 Hz);

MS (FAB) m/z: 383 (M+H)⁺.

(2b) Allyl2,3,6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-4,6-O-benzylidene-β-D-glucopyranosyl)-D-glucopyranoside

The compound (24.8 g, 64.9 mmol) synthesized in Example 2 (2a) wasdissolved in N,N-dimethylformamide (300 mL) and benzaldehydedimethylacetal (13 mL, 84.4 mmol) and p-toluenesulfonic acid monohydrate(617 mg, 3.24 mmol) were added thereto, followed by stirring of themixture at 20 mmH g and 50° C. for 5 hours. After triethylamine (900 μL)was added to the reaction mixture, the solvent was distilled off underreduced pressure. Water (100 mL) was added to the residue and themixture was extracted with ethyl acetate (200 mL×5). After the extractwas washed with saturated brine (100 mL) and dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (400 mL) and sodiumhydride (20 g, 0.45 mmol) was added thereto under ice-cooling, followedby stirring of the mixture at the same temperature for 10 minutes.Benzyl bromide (54 mL, 0.45 mmol) was added thereto and the mixture wasstirred at room temperature for 2.5 hours. Water (100 mL) was added tothe reaction mixture and the mixture was extracted with ethyl acetate(500 mL). After the extract was washed with water (100 mL) and saturatedbrine (50 mL) and dried with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 10:1-7:1,V/V) to obtain the desired title compound (46.6 g, yield 78%) as a paleyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.10-5.00 (26H, m), 5.18 (1H, d, J=11.7 Hz),5.35 (1H, d, J=17.6 Hz), 5.60 (1H, s), 5.95 (1H, ddd, J=17.6, 11.7, 5.9Hz), 7.20-7.60 (30H, m);

MS (FAB) m/z: 922 (M+H)⁺.

(2c) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (63.0 g, 68.4 mmol) synthesized in Example 2 (2b) wasdissolved in diethyl ether (800 mL) and methylene chloride (400 mL) andlithium aluminium hydride (10.4 g, 0.27 mol) and aluminium chloride(III) (36.4 g, 0.27 mol) were added thereto, followed by heating of themixture under reflux for 1 hour. After the reaction mixture was dilutedwith diethyl ether (500 mL). 1N aqueous sodium hydroxide solution (21.0mL) was added to the reaction mixture and the mixture was stirred for 1hour. After extraction with ethyl acetate, the organic layer was washedwith 10% aqueous hydrochloric acid solution (500 mL), saturated aqueoussodium hydrogencarbonate solution (500 mL) and saturated brine (300 mL)and dried with anhydrous sodium sulfate, followed by distilling off ofthe solvent reduced pressure. The residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 4:1-3:1-2:1, V/V) toobtain the desired title compound (37.8 g, yield 60%) as a pale yellowsolid.

¹H NMR (400 MHz, CDCl₃): δ 3.10-5.00 (29H, m), 5.18 (1H, d, J=10.8 Hz),5.35 (1H, d, J=22.5 Hz), 5.95 (1H, ddd, J=22.5, 10.8, 5.9 Hz), 7.20-7.60(30H, m);

MS (FAB) m/z: 924 (M+H)⁺.

(2d) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-toluenesulfonyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (37.8 g, 41.0 mmol) synthesized in Example 2 (2c) wasdissolved in pyridine (300 mL) and p-toluenesulfonyl chloride (15.6 g,82.0 mmol) and 4-dimethylaminopyridine (1.0 g, 0.82 mmol) were addedthereto, followed by stirring of the mixture at room temperature for 13hours. After the solvent was distilled off under reduced pressure, theresidue was poured to 10% aqueous hydrochloric acid solution (50 mL) andethyl acetate (200 mL) and the organic layer was washed with 10% aqueoushydrochloric acid solution (50 mL), saturated aqueous sodiumhydrogencarbonate solution (20 mL) and saturated brine (20 mL) and driedwith anhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain thedesired title compound (32.6 g, yield 74%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 2.35 (3H, s), 3.10-5.00 (28H, m), 5.18 (1H,d, J=10.8 Hz), 5.35 (1H, d, J=22.5 Hz), 5.95 (1H, ddd, J=22.5, 10.8, 5.9Hz), 7.10-7.65 (34H, m);

MS (FAB) m/z: 1078 (M+H)⁺.

(2e) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (32.6 g, 30.3 mol) synthesized in Example 2 (2d) wasdissolved in diethyl ether (600 mL) and lithium aluminium hydride (1.72g, 45.4 mol) was added thereto, followed by heating of the mixture underreflux for 1 hour. After the reaction mixture was diluted with diethylether (200 mL), 1N aqueous NaOH solution (2.0 mL) and water (2.0 mL)were added thereto, followed by stirring of the mixture for 30 minutes.After celite filtration, the solvent was distilled off under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 7:1-6:1, V/V) to obtain thedesired title compound (15.0 g, yield 55%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H, d, J=6.0 Hz), 3.10-5.00 (26H, m),5.20 (1H, d, J=10.8 Hz), 5.35 (1H, d, J=22.5 Hz), 5.95 (1H, ddd, J=22.5,10.8, 5.9 Hz), 7.10-7.65 (30H, m);

MS (FAB) m/z: 908 (M+H)⁺.

(2f)2,3,6-tri-O-Benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (15.0 g, 16.5 mmol) synthesized in Example 2 (2e) wasdissolved in methanol (150 mL) and tetrahydrofuran (30 mL) and palladiumchloride (II) (586 mg, 3.31 mmol) was added thereto, followed bystirring of the mixture at room temperature for 14 hours. After thereaction mixture was subjected to celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate,5:1-4:1-3:1, V/V) to obtain the desired title compound (12.0 g, yield84%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.19-1.22 (3H, m), 2.96-3.66 (8H, m),3.77-4.02 (3H, m), 4.34-4.37 (2H, m), 4.54-4.89 (10H, m), 5.00-5.19 (2H,m), 7.23-7.45 (30H, m);

MS (FAB) m/z: 868 (M+H)⁺.

(2g) Benzyl(2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranosyl]oxy}pyrrolidine-1-carboxylate

The compound (18.8 g, 21.8 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (400 mL) and trichloroacetonitrile (10.9mL, 109 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.33 mL, 2.18mmol) were added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (19.8 g, 90%) of colorless oil. The compound (9.5 g, 21.2mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (480mL) and trimethylsilyl trifluoromethanesulfonate (0.38 mL, 2.12 mmol)was dissolved in diethyl ether (20 mL) under a nitrogen atmosphere andthe mixture was added thereto. A solution of imidate in diethyl ether(100 mL) was added to the reaction mixture and the mixture was stirredat room temperature for 3 hours. After triethylamine (0.35 mL, 2.54mmol) was added to the reaction mixture and the solvent was distilledoff under reduced pressure, the mixture was diluted with ethyl acetate(200 mL) and washed with saturated aqueous sodium hydrogencarbonate (200mL) and saturated brine (200 mL). After the organic layer was dried withanhydrous sodium sulfate, the solvent was distilled off under reducedpressure and the residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 3:1, V/V) to obtain the desiredtitle compound (13.3 g, 47%) and its β isomer (4.5 g, 16%) as acolorless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H, d, J=5.9 Hz), 3.10-3.22 (2H, m),3.30-3.38 (2H, m), 3.42 (1H, t, J=8.8 Hz), 3.50-3.70 (5H, m), 3.76-3.87(5H, m), 4.01-4.10 (1H, m), 4.26-4.51 (9H, m), 4.61 (1H, d, J=11.0 Hz),4.69-4.88 (8H, m), 4.96-5.16 (3H, m), 7.19-7.34 (43H, m), 7.43 (2H, d,J=7.3 Hz);

MS (FAB) m/z: 1318 (M+Na)⁺.

(2h) (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (13.3 g, 10.3 mmol) synthesized in Example 2 (2g) wasdissolved in 1% hydrochloric acid methanol solution (250 mL) and 20%palladium hydroxide-carbon (4 g) was added thereto, followed by stirringof the mixture under a hydrogen atmosphere for 2 hours. After thecatalyst was removed by celite filtration, 28% ammonia water (5 mL) wasadded thereto and the mixture was stirred for 10 minutes. After thesolvent was distilled off under reduced pressure and the residue waspassed through ion exchange resin (Dowex 50w×8) column with water (200mL), 1% ammonia water (200 mL) was flowed through. The ammonia watercontaining the desired compound was concentrated under reduced pressureand was purified using silica gel flash column chromatography (ethylacetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired titlecompound (1.6 g, 35%) as a colorless solid.

[α]D²⁰ +88.8 (c 0.52, H₂O);

¹H NMR (500 MHz, D₂O): δ 1.22 (3H, d, J=6.8 Hz), 2.88 (1H, m), 3.07-3.16(3H, m), 3.21 (1H, dd, J=7.8, 7.8 Hz), 3.36 (1H, dd, J=9.8, 9.8 Hz),3.42 (1H, m), 3.49-3.55 (2H, m), 3.61-3.72 (5H, m), 3.75-3.83 (2H, m),3.89 (1H, m), 4.24 (1H, m), 4.38 (1H, d, J=7.9 Hz), 5.02 (1H, d, J=3.9Hz);

¹³C NMR (D₂O): δ 16.9, 51.7, 60.0, 61.8, 64.7, 71.0, 71.1, 71.6, 72.2,73.6, 75.0, 75.5, 75.9, 79.2, 84.3, 97.4, 102.7;

MS (FAB) m/z: 442 (M+H)⁺.

Example 3 (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl4-O-β-D-glucopyranosyl-α-D-glucopyranoside (Exemplification compound No.1-155)

(3a) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-D-glucopyranoside

α-D-Cellobiose octaacetate (4.15 g, 6.12 mmol) was dissolved inmethylene chloride (50 mL) and allyl alcohol (2.09 mL, 30.6 mmol) andtrimethylsilyl trifluoromethanesulfonate (1.11 mL, 6.12 mmol) were addedthereto under ice-cooling, followed by stirring of the mixture at roomtemperature for 4 hours. After water (20 mL) was added to the reactionmixture and the mixture was extracted with methylene chloride (50 mL),the organic layer was washed with saturated brine (20 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was dissolved in methanol (40 mL)and sodium methoxide (2.36 mL, 12.2 mmol) was added thereto underice-cooling, followed by stirring of the mixture at room temperature for1 hour. After Dowex 50w×8 was added until the reaction mixture becameneutral and the mixture was filtered, the solvent was distilled offunder reduced pressure. The residue was dissolved inN,N-dimethylformamide (60 mL) and sodium hydride (2.67 g, 61.2 mmol) wasadded thereto under ice-cooling, followed by stirring of the mixture atthe same temperature for 10 minutes. Benzyl bromide (8.01 mL, 67.3 mmol)was added thereto and the mixture was stirred at room temperature for 2hours. After water (40 mL) was added thereto and the mixture wasextracted with ethyl acetate (200 mL), the organic layer was washed withwater (40 mL) and saturated brine (20 mL) and dried with anhydroussodium sulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 20:1-10:1-8:1, V/V) to obtain thedesired title compound (4.85 g, yield 78%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.29-3.71 (10H, m), 3.80-4.15 (3H, m),4.36-4.61 (8H, m), 4.67-4.89 (8H, m), 5.04-5.11 (1H, m), 5.17-5.22 (1H,m), 5.29-5.34 (1H, m), 5.91-5.98 (1H, m), 7.07-7.41 (35H, m);

MS (FAB) m/z: 1014 (M+H)⁺.

(3b)2,3,6-tri-O-Benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (4.85 g, 4.79 mmol) synthesized in Example 3 (3a) wasdissolved in dimethylsulfoxide (40 mL) and potassium t-butoxide (2.15 g,19.2 mmol) was added thereto, followed by stirring of the mixture at110° C. for 1 hour. After water (30 mL) was added to the reactionmixture and the mixture was extracted with ethyl acetate (150 mL), theorganic layer was washed with saturated brine (20 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was dissolved in 1,4-dioxane (36 mL)and 16% aqueous sulfuric acid solution (3 mL) was added thereto,followed by stirring of the mixture at 100° C. for 1 hour. After water(30 mL) was added to the reaction mixture and the mixture was extractedwith ethyl acetate (150 mL), the organic layer was washed with saturatedbrine (20 mL) and dried with anhydrous sodium sulfate, followed bydistilling off of the solvent under reduced pressure. The residue waspurified using silica gel flash column chromatography (hexane:ethylacetate, 4:1 3:1, V/V) to obtain the desired title compound (3.15 g,yield 68%) as a brown oil.

¹H NMR (400 MHz, CDCl₃): δ 2.96-3.95 (9H, m), 4.30-4.38 (3H, m),4.45-4.81 (7H, m), 4.98-5.10 (1H, m), 7.09-7.32 (35H, m);

MS (FAB) m/z: 974 (M+H)⁺.

(3c)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (537 mg, 0.55 mmol) synthesized in Example 3 (3b) wasdissolved in methylene chloride (15 mL) and trichloroacetonitrile (277μL, 2.76 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (611 mg, 99%) as a yellow oil. The compound (223 mg, 0.50mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (10mL) and trimethylsilyl trifluoromethanesulfonate (9 μL, 0.05 mmol) wasadded thereto. A solution of imidate (611 mg, 0.55 mmol) in diethylether (4 mL) was added dropwise thereto and the mixture was stirred atroom temperature for 45 minutes. After triethylamine (4 drops) was addedto the reaction mixture, the solvent was distilled off under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 2:1, V/V) to obtain the desiredtitle compound (395 mg, 57%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 3.24-3.86 (17H, m), 4.00-4.10 (2H, m),4.25-4.54 (11H, m), 4.66-4.87 (8H, m), 4.95-5.12 (3H, m), 7.12-7.39(50H, m);

MS (FAB) m/z: 1402 (M+H)⁺.

(3d) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-β-D-glucopyranosyl-α-D-glucopyranoside

The compound (611 mg, 0.55 mmol) synthesized in Example 3 (3c) wasdissolved in methanol (8 mL) and ethyl acetate (2 mL) and hydrochloricacid-methanol solution (2 mL) and 20% palladium hydroxide-carbon (400mg) were added thereto, followed by stirring of the mixture at roomtemperature under a hydrogen atmosphere for 4 hours. After the celitefiltration, the solvent was distilled off under reduced pressure andmethanol (2 mL) and 28% ammonia water (300 μL) were added thereto,followed by stirring of the mixture at room temperature for 10 minutes.After the solvent was distilled off under reduced pressure, the residuewas purified by ion exchange resin (Dowex 50w×8) column (water −1.4%ammonia water). Further, it was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain thedesired title compound (54 mg, 42%) as colorless amorphous matter.

[α]D20 +91.9 (c 0.38, D₂O);

¹H NMR (400 MHz, D₂O): δ 2.90 (1H, dd, J=12.5, 2.2 Hz), 3.11 (1H, dd,J=12.5, 5.1 Hz), 3.16-3.22 (2H, m), 3.28-3.43 (3H, m), 3.49-3.82 (10H,m), 3.88-3.91 (1H, m), 4.23-4.27 (1H, m), 4.40 (1H, d, J=8.1 Hz), 5.01(1H, d, J=4.4 Hz);

MS (FAB) m/z: 458 (M+H)⁺.

Example 4 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-fluoro-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside(Exemplification compound No. 1-278)

(4a) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (6.43 g, 6.97 mmol) synthesized in Example 2 (2c) wasdissolved in 1,2-dimethoxyethane (130 mL) and diethylaminosulfurtrifluoride (2 mL, 20.50 mmol) was added thereto, followed by stirringof the mixture at 60° C. for 1 hour. Methanol (10 mL) was added to thereaction mixture under ice-cooling and the mixture was stirred for 30minutes. After ethyl acetate (50 mL) was added thereto and the organiclayer was washed with saturated aqueous sodium hydrogencarbonatesolution (50 mL) and saturated brine (50 mL) and dried with anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The residue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1, V/V) to obtain the desired title compound(5.06 g, yield 78%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.00-5.20 (28H, m), 5.25 (1H, d, J=8.0 Hz),5.40 (1H, d, J=16.0 Hz), 6.00 (1H, m), 7.20-7.60 (30H, m);

MS (FAB) m/z: 926 (M+H)⁺.

(4b) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (5.06 g, 5.47 mmol) synthesized in Example 4 (4a) wasdissolved in methanol (75 mL) and tetrahydrofuran (15 mL) and palladiumchloride (II) (190 mg, 1.09 mmol) was added thereto, followed bystirring of the mixture at room temperature for 14 hours. After thereaction mixture was subjected to celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate,4:1-3:1-2:1, V/V) to obtain the desired title compound (3.07 g, yield63%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.10-5.20 (27H, m), 7.20-7.60 (30H, m);

MS (FAB) m/z: 886 (M+H)⁺.

(4c)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-(benzyloxymethyl)pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (646.0 mg, 0.73 mmol) synthesized in Example 4 (4b) wasdissolved in methylene chloride (12 mL) and trichloroacetonitrile (0.38mL, 3.66 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 drop) wereadded thereto, followed by stirring of the mixture at room temperaturefor 30 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, 1% triethylamine, V/V) toobtain imidate (740.2 mg, 98.5%) of yellow oil. The compound (326.7 mg,0.73 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether(13 mL) and trimethylsilyl trifluoromethanesulfonate (6.6 μL, 0.037mmol) was dissolved in diethyl ether (2 mL) under a nitrogen atmosphereand the mixture was added thereto. A solution of imidate (740.2 mg) indiethyl ether (5 mL) was added to the reaction mixture and the mixturewas stirred at room temperature for 2 hours. After triethylamine (5.0μL, 0.036 mmol) was added to the reaction mixture and the solvent wasdistilled off under reduced pressure, the residue was diluted with ethylacetate (20 mL) and washed with saturated aqueous sodiumhydrogencarbonate (20 mL) and saturated brine (20 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure and the residue containing α,β-mixture waspurified using silica gel flash column chromatography (hexane:ethylacetate, 6:1, V/V) to isolate the desired title compound a form (126.0mg, 13%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 3.00-5.20 (39H, m), 7.00-7.60 (45H, m);

MS (FAB) m/z: 1315 (M+H)⁺.

(4d) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-fluoro-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (126.0 mg, 0.096 mmol) synthesized in Example 4 (4c) wasdissolved in methanol (10 mL) containing 1% aqueous hydrochloric acidsolution and 20% palladium hydroxide-carbon (100 mg) was added thereto,followed by stirring of the mixture under a hydrogen atmosphere for 2hours. After the solvent was removed by celite filtration, 28% ammoniawater (0.5 mL) was added thereto, followed by stirring of the mixturefor 10 minutes. After the solvent was distilled off under reducedpressure and the aqueous solution (100 mL) was subjected to ion exchangeresin (Dowex 50w×8), it was eluted with 1% ammonia water (100 mL). Theammonia water containing the desired compound was concentrated underreduced pressure and the residue was purified using silica gel flashcolumn chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V)to obtain the desired title compound (23.1 mg, 52%) as colorlessamorphous matter.

[α]D20 +49.6 (c 0.30, H₂O);

¹H NMR (400 MHz, D₂O): δ 3.00-3.07 (1H, m), 3.20-3.27 (2H, m) 3.30-3.80(21H, m), 3.95 (1H, s), 4.29 (1H, brs), 4.43 (1H, d, J=8.0 Hz),4.50-4.80 (2H, m), 5.00 (1H, d, J=4.0 Hz);

MS (FAB) m/z: 460 (M+H)⁺.

Example 5 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-fluoro-6-deoxy-β-D-glucopyranosyl)-6-fluoro-6-deoxy-α-D-glucopyranoside(Exemplification compound No. 1-280)

(5a) Allyl6-O-t-butyldimethylsilyl-2,3-di-O-benzyl-4-O-(6-O-t-butyldimethylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (7.76 g, 20.30 mmol) synthesized in Example 2 (2a) wasdissolved in N,N-dimethylformamide (160 mL) and t-butyldimethylsilylchloride (7.65 mL, 50.75 mmol) and imidazole (4.15 g, 60.90 mmol) wereadded thereto, followed by stirring of the mixture at room temperaturefor 1 hour. After water (50 mL) was added to the reaction mixture andthe mixture was extracted with ethyl acetate (100 mL), it was washedwith a saturated brine (50 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (120 mL) and sodiumhydride (4.0 g, 91.67 mmol) was added thereto under ice-cooling,followed by stirring of the mixture at the same temperature for 10minutes. Benzyl bromide (11 mL, 92.48 mmol) was added thereto and themixture was stirred at room temperature for 3 hours. After water (50 mL)was added to the reaction mixture and the mixture was extracted withethyl acetate (150 mL), the organic layer was washed with water (50 mL)and saturated brine (50 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 12:1, V/V) to obtain the desired title compound(8.67 g, yield 89%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.00-0.20 (12H, m), 0.90-1.00 (18H, m),3.00-5.20 (26H, m), 5.20 (1H, d, J=8.0 Hz), 5.35 (1H, d, J=16.0 Hz),6.00 (1H, m), 7.20-7.60 (25H, m);

MS (FAB) m/z: 1062 (M+H)⁺.

(5b) Allyl2,3-di-O-benzyl-4-O-(2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (8.67 g, 8.17 mmol) synthesized in Example 5 (5a) wasdissolved in tetrahydrofuran (150 mL) and a solution of 1.0 M tetrabutylammonium fluoride in THF (20 mL, 20 mmol) was added thereto, followed bystirring of the mixture at room temperature for 5 hours. After thesolvent was distilled off under reduced pressure, the residue waspurified using silica gel flash column chromatography (methylenechloride:methanol, 50:1, V/V) to obtain the desired title compound (4.19g, yield 62%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.00-5.20 (28H, m), 5.20 (1H, d, J=12.0 Hz),5.30 (1H, d, J=18.0 Hz), 5.98 (1H, m), 7.20-7.40 (25H, m);

MS (FAB) m/z: 833 (M+H)⁺.

(5c) Allyl2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (4.19 g, 5.03 mmol) synthesized in Example 5 (5b) wasdissolved in 1,2-dimethoxyethane (85 mL) and diethylaminosulfurtrifluoride (2.5 mL, 25.61 mmol) was added thereto, followed by stirringof the mixture at 60° C. for 1 hour. Methanol (10 mL) was added to thereaction mixture under ice-cooling and the mixture was stirred for 30minutes. After ethyl acetate (50 mL) was added thereto and the organiclayer was washed with saturated aqueous sodium hydrogencarbonatesolution (50 mL) and saturated brine (50 mL) and dried with anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The residue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 5:1-4:1, V/V) to obtain the desired titlecompound (2.23 g, yield 53%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.00-5.10 (26H, m), 5.23 (1H, m), 5.33 (1H,m), 5.95 (1H, m), 7.20-7.40 (25H, m);

MS (FAB) m/z: 837 (M+H)⁺.

(5d) Allyl2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (2.23 g, 2.66 mmol) synthesized in Example 5 (5c) wasdissolved in acetic acid (20 mL) and water (1 mL) and palladium chloride(II) (0.47 g, 2.65 mmol) and sodium acetate (0.87 g, 10.61 mmol) wereadded thereto, followed by stirring of the mixture at room temperaturefor 14 hours. After the reaction mixture was subjected to celitefiltration, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate 3:1, V/V) to obtain the desired title compound(0.73 g, yield 34%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.00-5.10 (25H, m), 7.20-7.60 (25H, m);

MS (FAB) m/z: 797 (M+H)⁺.

(5e)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-(benzyloxymethyl)pyrrolidin-3-yl2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (730.0 mg, 0.92 mmol) synthesized in Example 5 (5d) wasdissolved in methylene chloride (13.5 mL) and trichloroacetonitrile(0.46 mL, 4.60 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (1 drop)were added thereto, followed by stirring of the mixture at roomtemperature for 30 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, 1% triethylamine, V/V) toobtain imidate (675.3 mg, 78%) of yellow oil. The compound (412.3 mg,0.92 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether(13 mL) and trimethylsilyl trifluoromethanesulfonate (8.3 μL, 0.046mmol) was dissolved in diethyl ether (2 mL) under a nitrogen atmosphereand the mixture was added. Subsequently, a solution of imidate (675.3mg) in diethyl ether (5 mL) was added to the reaction mixture and themixture was stirred at room temperature for 2 hours. After triethylamine(7.0 μL, 0.050 mmol) was added to the reaction mixture and the solventwas distilled off under reduced pressure, the residue was diluted withethyl acetate (20 mL) and the mixture was washed with saturated aqueoussodium hydrogencarbonate (20 mL) and saturated brine (20 mL). After theorganic layer was dried with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue containing α,β-mixturewas purified using silica gel flash column chromatography (hexane:ethylacetate, 6:1, V/V) to isolate the desired title compound a form (122.6mg, 11%) thereof as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.00-5.20 (37H, m), 7.00-7.60 (40H, m);

MS (FAB) m/z: 1227 (M+H)⁺.

(5f) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-fluoro-6-deoxy-β-D-glucopyranosyl)-6-fluoro-6-deoxy-α-D-glucopyranoside

The compound (122.6 mg, 0.10 mmol) synthesized in Example 5 (5e) wasdissolved in methanol (10 mL) containing 1% aqueous hydrochloric acidsolution and 20% palladium hydroxide-carbon (100 mg) was added thereto,followed by stirring of the mixture under a hydrogen atmosphere for 2hours. After the catalyst was removed by celite filtration, 28% ammoniawater (0.5 mL) was added thereto and the mixture was stirred for 10minutes. After the solvent was distilled off under reduced pressure andthe aqueous solution (100 mL) was subjected to ion exchange resin (Dowex50w×8) column, it was eluted with 1% ammonia water (100 mL). The ammoniawater containing the desired compound was concentrated under reducedpressure and the residue was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) toobtain the desired title compound (25.9 mg, 56%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 3.20-3.90 (22H, m), 4.10 (1H, s), 4.41 (1H, d,J=8.1 Hz), 4.50-4.80 (4H, m), 5.05 (1H, d, J=6.3 Hz);

MS (FAB) m/z: 462 (M+H)⁺.

Example 6 (1S,3R,4R,5S)-1-Amino-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 5-28)

(6a) Methyl 4,6-O-benzylidene-3-O-benzyl-2-deoxy-D-glucopyranoside

2-Deoxy-D-glucose (10.1 g, 61.5 mmol) was dissolved in methanol (100 mL)and hydrochloric acid-methanol solution (50 mL) was added thereto,followed by heating of the mixture under reflux for 3 hours. Aftercooling to room temperature, triethylamine was added thereto until thereaction mixture became basic and the solvent was distilled off underreduced pressure. The residue was dissolved in N,N-dimethylformamide(100 mL) and benzaldehyde dimethylacetal (12.9 mL, 86.1 mmol) andp-toluenesulfonic acid monohydrate (585 mg, 3.08 mmol) were addedthereto, followed by stirring of the mixture at 20 mmHg and 50° C. for 3hours. After cooling to room temperature, water (50 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate (200mL). The organic layer was washed with water (50 mL) and saturated brine(30 mL) and dried with anhydrous sodium sulfate, followed by distillingoff of the solvent under reduced pressure. The residue was dissolved inN,N-dimethylformamide (100 mL) and 55% sodium hydride (3.99 g, 92.3mmol) was added thereto under ice-cooling, followed by stirring of themixture at the same temperature for 10 minutes. Benzyl bromide (11.0 mL,92.3 mmol) was added thereto and the mixture was stirred at roomtemperature for 19 hours. After water (50 mL) was added to the reactionmixture and the mixture was extracted with ethyl acetate (200 mL), theorganic layer was washed with water (50 mL) and saturated brine (30 mL)and dried with anhydrous sodium sulfate, followed by distilling off ofthe solvent under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 20:1-10:1,V/V) to obtain the desired title compound (16.0 g, yield 73%) as ayellow solid.

¹H NMR (400 MHz, CDCl₃): δ 1.66-1.83 (1H, m), 2.24-2.34 (1H, m), 3.33(3H, s), 3.65-3.85 (3H, m), 3.98-4.04 (1H, m), 4.22-4.35 (1H, m),4.66-4.84 (3H, m), 5.60-5.62 (1H, m), 7.23-7.40 (8H, m) 7.49-7.52 (2H,m);

MS (FAB) m/z: 357 (M+H)⁺.

(6b) Methyl 3-O-benzyl-2-deoxy-D-glucopyranoside

The compound (2.00 g, 5.62 mmol) synthesized in Example 6 (6a) wasdissolved in acetic acid (15 mL) and water (5 mL) and the mixture wasstirred at 60° C. for 2 hours and 30 minutes. After cooling to roomtemperature, the solvent was distilled off under reduced pressure andthe residue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 2:1-1:2, V/V) to obtain the desired titlecompound (1.33 g, yield 88%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.49-1.64 (1H, m), 2.11 (1H, brs), 2.25-2.36(1H, m), 2.62 (1H, brs), 3.33 (3H, s), 3.44-3.65 (2H, m), 3.76-3.87 (3H,m), 4.41-4.52 (1H, m), 4.65-4.71 (1H, m), 4.81-4.82 (1H, m), 7.26-7.37(5H, m);

MS (FAB) m/z: 267 (M−H)⁺.

(6c) Methyl 3-O-benzyl-2-deoxy-6-O-p-toluenesulfonyl-D-glucopyranoside

The compound (12.2 g, 45.3 mmol) synthesized in Example 6 (6b) wasdissolved in pyridine (100 mL) and p-toluenesulfonyl chloride (13 g,68.0 mmol) and 4-dimethylaminopyridine (553 mg, 4.53 mmol) were addedthereto, followed by stirring of the mixture at room temperature for 12hours. The reaction mixture was poured to 10% aqueous hydrochloric acidsolution (80 mL) under ice cooling, and ethyl acetate (200 mL) and theorganic layer was washed with 10% aqueous hydrochloric acid solution (80mL), saturated aqueous sodium hydrogencarbonate solution (80 mL) andsaturated brine (50 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired titlecompound (16.9 g, yield: 88%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.54-1.61 (1H, m), 2.20-2.28 (1H, m), 2.44(3H, s), 3.27 (3H, s), 3.41-3.48 (2H, m), 3.70-3.76 (2H, m), 4.22-4.41(2H, m), 4.47-4.57 (1H, m), 4.63-4.68 (1H, m), 4.75-4.76 (1H, m),7.26-7.36 (7H, m), 7.79-7.84 (2H, m);

MS (FAB) m/z: 421 (M−H)⁺.

(6d) Methyl4-O-benzoyl-3-O-benzyl-2-deoxy-6-O-p-toluenesulfonyl-D-glucopyranoside

The compound (16.9 g, 40.0 mmol) synthesized in Example 6 (6c) wasdissolved in methylene chloride (150 mL) and triethylamine (22 mL, 0.16mol), benzoyl chloride (14 mL, 0.12 mol) and 4-dimethylaminopyridine(489 mg, 4.00 mmol) were added thereto, followed by stirring of themixture at room temperature for 18 hours. After water (80 mL) was addedto the reaction mixture and the mixture was extracted with methylenechloride (100 mL), the organic layer was washed with saturated brine (50mL) and dried with anhydrous sodium sulfate, followed by distilling offof the solvent under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 4:1-3:1,V/V) to obtain the desired title compound (20.8 g, yield 99%) as ayellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.71-1.78 (1H, m), 2.26-2.31 (1H, m), 2.33(3H, s), 3.32 (3H, s), 3.94-4.14 (4H, m), 4.40-4.44 (1H, m), 4.52-4.59(1H, m), 4.80-4.81 (1H, m), 5.03-5.08 (1H, m), 7.09-7.20 (6H, m),7.40-7.49 (3H, m), 7.57-7.62 (1H, m), 7.66-7.71 (2H, m), 7.87-7.96 (2H,m);

MS (FAB) m/z: 527 (M+H)⁺.

(6e) Methyl 4-O-benzoyl-3-O-benzyl-2,6-dideoxy-6-iode-D-glucopyranoside

The compound (2.53 g, 4.81 mmol) synthesized in Example 6 (6d) wasdissolved in toluene (30 mL) and sodium iodide (3.6 g, 24.0 mmol) and18-crown-6-ether (254 mg, 0.96 mmol) were added thereto, followed bystirring of the mixture at 100° C. under a nitrogen atmosphere for 3hours. After cooling to room temperature, water (30 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate (100mL). The organic layer was washed with saturated brine (30 mL) and driedwith anhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 15:1-10:1, V/V) to obtainthe desired title compound (2.11 g, yield 91%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.72-1.86 (1H, m), 2.31-2.41 (1H, m),3.17-3.26 (1H, m), 3.33-3.40 (1H, m), 3.45 (3H, s), 3.69-3.86 (1H, m),3.99-4.31 (1H, m), 4.44-4.48 (1H, m), 4.57-4.62 (1H, m), 4.90-4.91 (1H,m), 5.03-5.18 (1H, m), 7.13-7.26 (5H, m), 7.43-7.49 (2H, m), 7.58-7.62(1H, m), 8.02-8.04 (2H, m);

MS (FAB) m/z: 483 (M+H)⁺.

(6f) 4-O-Benzoyl-3-O-benzyl-2,5,6-trideoxy-D-xylo-hex-5-enose oxime

The compound (2.11 g, 4.38 mmol) synthesized in Example 6 (6e) wasdissolved in isopropanol (50 mL) and water (2 mL) and zinc powder (2 g)washed with 5% aqueous hydrochloric acid solution was added thereto,followed by heating of the mixture under reflux for 25 minutes. Aftercooling to room temperature, it was subjected to celite filtration andthe solvent was distilled off under reduced pressure. The residue wasdissolved in ethanol (50 mL) and hydroxylamine hydrochloride (913 mg,13.1 mmol) and pyridine (1.06 mL, 13.1 mmol) were added thereto,followed by stirring of the mixture at 60° C. for 50 minutes. Aftercooling to room temperature, the solvent was distilled off under reducedpressure and water (20 mL) was added thereto. After the mixture wasextracted with ethyl acetate (100 mL), the organic layer was washed withsaturated brine (20 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1-5:1-4:1-3:1, V/V) to obtain the desired titlecompound (1.14 g, yield 77%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 2.47-2.55 (1H, m), 2.61-2.79 (1H, m), 3.88(0.5H, dt, J=8.1, 5.1 Hz), 3.94 (0.5H, dt, J=8.1, 4.4 Hz), 4.65 (0.5H,d, J=11.7 Hz), 4.67 (0.5H, d, J=11.7 Hz), 4.74 (0.5H, d, J=11.7 Hz),4.75 (0.5H, d, J=11.7 Hz), 5.33-5.36 (1H, m), 5.41-5.47 (1H, m),5.74-5.77 (1H, m), 6.01 (1H, ddd, J=16.8, 5.9, 5.1 Hz), 6.84 (0.5H, t,J=5.1 Hz), 7.26-7.33 (5H, m), 7.43-7.48 (2.5H, m), 7.56-7.60 (1H, m),8.06-8.08 (2H, m);

MS (FAB) m/z: 340 (M+H)⁺.

(6g)(3aR,4R,5R,6aS)-4-Benzoyloxy-5-benzyloxy-hexahydro-cyclopenta[c]isoxazole(3aS,4R,5R,6aR)-4-benzoyloxy-5-benzyloxy-hexahydro-cyclopenta[c]isoxazole

The compound (5.0 g, 14.7 mmol) synthesized in Example 6 (6f) wasdissolved in toluene (100 mL) and the mixture was heated under refluxfor 40 hours. After cooling to room temperature, the solvent wasdistilled off under reduced pressure and the residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 2:1-1:1,V/V) to obtain the desired title compound (mixture) (4.08 g, yield 82%)as an orange-color oil.

¹H NMR (400 MHz, CDCl₃): δ 1.92 (0.3H, ddd, J=10.2, 5.1, 5.1 Hz),2.00-2.13 (1.4H, m), 2.28-2.35 (0.3H, m), 2.99-3.01 (0.3H, m), 3.37(0.7H, dd, J=8.8, 7.3 Hz), 3.43-3.49 (0.7H, m), 3.99-4.22 (4.3H, m),4.63 (0.3H, d, J=11.7 Hz), 4.63 (1.4H, s), 4.67 (0.3H, d, J=9.5 Hz),5.21 (0.3H, t, J=3.7 Hz), 5.28 (0.7H, d, J=3.7 Hz), 7.25-7.35 (5H, m),7.43-7.47 (2H, m), 7.54-7.60 (1H, m), 7.99-8.08 (2H, m);

MS (FAB) m/z: 340 (M+H)⁺.

(6h)(3aR,4R,5R,6aS)-5-Benzyloxy-1-benzyloxycarbonyl-4-hydroxy-hexahydro-cyclopenta[c]isoxazole

The compound (4.08 g, 12.0 mmol) synthesized in Example 6 (6 g) wasdissolved in methanol (40 mL) and sodium methoxide (696 μL, 3.61 mmol)was added thereto, followed by stirring of the mixture at roomtemperature for 2 hours. After Dowex 50W×8 was added thereto until thereaction mixture became neutral and it was filtered, the solvent wasdistilled off under reduced pressure. The residue was dissolved in ethylacetate (40 mL) and saturated aqueous sodium hydrogencarbonate solution(20 mL) and benzyloxy chloroformate (2.4 mL, 16.8 mmol) were addedthereto under ice-cooling, followed by stirring of the mixture at thesame temperature for 1 hour and 30 minutes. The organic layer was washedwith saturated brine (50 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 2:1-1:1, V/V) to obtain the desired titlecompound (789 mg, yield 18%) as a pale yellow solid and its diastereomer(1.62 g, yield 36%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.57-1.63 (1H, m), 2.47 (1H, brs), 2.50-2.56(1H, m), 2.73-2.77 (1H, m), 3.61-3.69 (2H, m), 3.88-3.92 (1H, m), 4.01(1H, d, J=8.8 Hz), 4.49 (1H, d, J=11.7 Hz), 4.48-4.55 (1H, m), 4.60 (1H,d, J=11.7 Hz), 5.18 (2H, s);

MS (FAB) m/z: 370 (M+H)⁺.

(6i)(3aR,4R,5R,6aS)-5-Benzyloxy-1-benzyloxycarbonyl-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (751 mg, 0.87 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (15 mL) and trichloroacetonitrile (435μL, 4.33 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 1 hour. After the solvent was distilled off under reduced pressure,the residue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1-5:1, 1% triethylamine, V/V) to obtain imidate(734 mg, 84%) as a yellow oil. The compound (244 mg, 0.66 mmol)synthesized in Example 6 (6h) was dissolved in diethyl ether (12 mL) andtrimethylsilyl trifluoromethanesulfonate (12 μL, 0.07 mmol) was addedthereto. A solution of imidate (734 mg, 0.73 mmol) in diethyl ether (3mL) was added dropwise thereto, followed by stirring of the mixture atroom temperature for 1 hour. After triethylamine (4 drops) was added tothe reaction mixture, the solvent was distilled off under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 2:1-1:1, V/V) to obtain thedesired title compound (α,β mixture) (516 mg, yield 64%) as colorlessamorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.19 (1.5H, d, J=2.9 Hz), 1.20 (1.5H, d,J=2.9 Hz), 1.62-1.68 (0.5H, m), 1.79-1.84 (0.5H, m), 2.39-2.45 (0.5H,m), 2.48-2.53 (0.5H, m), 2.73-2.77 (0.5H, m), 2.85-2.86 (0.5H, m),3.10-3.60 (8H, m), 3.69-4.02 (6H, m), 4.10-4.14 (1H, m), 4.32-4.64 (8H,m), 4.69-4.87 (7H, m), 5.00 (0.5H, d, J=10.7 Hz), 5.12 (0.5H, d, J=3.9Hz), 5.18 (1H, d, J=10.7 Hz), 7.18-7.43 (50H, m);

MS (FAB) m/z: 1217 (M)⁺.

(6j)(3aR,4R,5R,6aS)-5-Benzyloxy-1-methyloxycarbonyl-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (516 mg, 0.42 mmol) synthesized in Example 6 (6i) wasdissolved in methanol (6 mL) and toluene (6 mL) and sodium methoxide(221 μL, 1.15 mmol) was added thereto, followed by stirring of themixture at 50° C. for 40 minutes. After cooling to room temperature,Dowex 50W×8 was added thereto until the reaction mixture became neutraland it was filtered, followed by distilling off of the solvent underreduced pressure. The residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 1.5:1-1:1, v/v) to obtain thedesired title compound (173 mg, yield 47%) as colorless amorphousmatter.

¹H NMR (400 MHz, CDCl₃): δ 1.61-1.69 (1H, m), 2.48-2.55 (1H, m),2.72-2.78 (1H, m), 3.13 (1H, dd, J=9.5, 8.8 Hz), 3.21 (1H, dd, J=9.5,5.9 Hz), 3.31 (1H, dd, J=8.1, 7.3 Hz), 3.36-3.54 (5H, m), 3.59-3.62 (1H,m), 3.79 (3H, s), 3.74-3.94 (5H, m), 3.99 (1H, d, J=8.8 Hz), 4.32-4.38(2H, m), 4.50-4.67 (7H, m), 4.76-5.00 (5H, m), 5.01 (1H, d, J=11.0 Hz),5.12 (1H, d, J=3.7 Hz), 7.14-7.44 (35H, m);

MS (FAB) m/z: 1141 (M)⁺.

(6k) (3aR,4R,5R,6aS)-5-Benzyloxy-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (363 mg, 0.32 mmol) synthesized in Example 6 (6j) wasdissolved in methanol (8 mL) and 1N aqueous potassium hydroxide solution(4 mL) was added thereto, followed by stirring of the mixture at 80° C.for 8 hours. After cooling to room temperature, saturated aqueousammonium chloride solution (15 mL) was added to the reaction mixture andthe mixture was extracted with ethyl acetate (100 mL). After the organiclayer was washed with saturated brine (10 mL) and dried with anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The residue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 1.5:1-1:1, V/V) to obtain the desired titlecompound (313 mg, yield 91%) as pale yellow amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H, d, J=5.9 Hz), 1.56-1.64 (1H, m),2.26-2.36 (1H, m), 2.76-2.86 (1H, m), 3.13 (1H, dd, J=9.5, 8.8 Hz),3.19-3.25 (2H, m), 3.32 (1H, dd, J=8.8, 8.1 Hz), 3.43-3.53 (3H, m),3.67-3.69 (2H, m), 3.81-3.95 (6H, m), 4.35-4.40 (2H, m), 4.51-4.67 (7H,m), 4.74-4.87 (6H, m), 5.01 (1H, d, J=10.3 Hz), 7.15-7.44 (35H, m);

MS (FAB) m/z: 1084 (M+H)⁺.

(6l) (1S,3R,4R,5S)-1-Amino-3-hydroxy-5-hydroxymethyl-cyclopenta-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (313 mg, 0.29 mmol) synthesized in Example 6 (6k) wasdissolved in methanol (8 mL) and ethyl acetate (4 mL) and hydrochloricacid (5 drops) and 20% palladium hydroxide-carbon (300 mg) were addedthereto, followed by stirring of the mixture at room temperature under ahydrogen atmosphere for 6 hours. After the celite filtration, thesolvent was distilled off under reduced pressure and methanol (3 mL) and28% water (300 μL) were added thereto, followed by stirring of themixture at room temperature for 10 minutes. After the solvent wasdistilled off under reduced pressure, the residue was purified by ionexchange column (Dowex 50W×8) (water-2.8% ammonia water). Further, itwas purified using silica gel flash column chromatography (ethylacetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound(107 mg, yield 81%) as a pale yellow solid.

¹H NMR (500 MHz, D₂O) δ 1.19 (1H, d, J=5.9 Hz), 1.53 (1H, dt, J=13.7,6.8 Hz), 2.18-2.23 (1H, m), 2.27-2.33 (1H, m), 3.07 (1H, dd, J=9.8, 8.8Hz), 3.19 (1H, dd, J=9.8, 7.8 Hz), 3.34 (1H, dd, J=9.8, 8.8 Hz),3.37-3.41 (1H, m), 3.47-3.51 (2H, m), 3.58 (1H, dd, J=14.7, 6.8 Hz),3.66-3.80 (6H, m), 3.86 (1H, dd, J=6.8, 4.9 Hz), 4.11-4.14 (1H, m), 4.36(1H, d, J=7.8 Hz), 5.06 (1H, d, J=3.9 Hz);

¹³C NMR (125 MHz, D₂O): δ 16.89, 38.27, 47.74, 49.85, 59.41, 60.05,70.97, 71.19, 71.56, 72.22, 73.64, 74.96, 75.45, 75.51, 79.24, 84.26,97.34, 102.68;

MS (FAB) m/z: 456 (M+H)⁺.

Example 7 (2R,3R,4R,5R)-2,5-Dihydroxymethyl-4-hydroxypyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-557)

(7a)(1R,3S,4S,6R,7R)-7-Benzyloxy-6-hydroxymethyl-3-methoxy-2-oxa-5-aza-bicyclo[2,2,1]heptane

Azide epoxide (Tetrahedron, 26, 1985, 1469) (2.03 g, 6.97 mmol) wasdissolved in ethanol (40 mL) and Lindlar catalyst (0.4 g) was addedthereto, followed by stirring of the mixture under a hydrogen atmospherefor 2 hours. After the catalyst was removed by celite filtration, it wasdissolved in ethanol (40 mL) and the mixture was heated under reflux for1 hour. After the solvent was distilled off under reduced pressure, theresidue was purified using silica gel flash column chromatography(methylene chloride:ethanol, 20:1-10:1, V/V) to obtain the desired titlecompound (1.21 g, yield 65%) as a brown solid.

¹H NMR (400 MHz, CDCl₃): δ 2.15-2.35 (2H, br), 3.19 (1H, dd, J=5.8, 5.9Hz), 3.35 (3H, s), 3.41 (1H, s), 3.65 (1H, dd, J=5.8, 11.7 Hz), 3.73(1H, dd, J=5.8, 11.7 Hz), 4.11 (1H, s), 4.18 (1H s), 4.54 (1H, d, J=11.7Hz), 4.61 (1H, d, J=11.7 Hz), 4.64 (1H, s), 7.29-7.38 (5H, m);

MS (FAB) m/z: 266 (M+H)⁺.

(7b)(1R,3R,4S,6R,7R)-7-Hydroxy-6-hydroxymethyl-3-methoxy-2-oxa-5-aza-bicyclo[2,2,1]heptane-5-carboxylicacid benzyl ester

The compound (930 mg, 3.51 mmol) synthesized in Example 7 (7a) wasdissolved in methanol (20 mL) and 20% palladium hydroxide-carbon (280mg) was added thereto, followed by stirring of the mixture under ahydrogen atmosphere for 6 hours. After the catalyst was removed bycelite filtration, the solvent was distilled off under reduced pressure.The residue was dissolved in ethyl acetate:saturated aqueous sodiumhydrogencarbonate solution (2:1, 20 mL) and benzyl chloroformate (0.75mL, 5.27 mmol) was added thereto, followed by stirring of the mixture at0° C. for 2 hours. After water (20 mL) was added thereto at 0° C. andthe mixture was extracted with ethyl acetate, the organic layer waswashed with saturated brine (20 mL) and dried with anhydrous sodiumsulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 1:1-3:1, V/V) to obtain thedesired title compound (759 mg, yield 70%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.33 (3H, s), 3.50-4.00 (3H, m), 4.10-4.25(3H, m), 4.61 (1H, brs), 4.60-4.74 (2H, m), 5.10-5.25 (2H, m), 7.25-7.45(5H, m);

MS (FAB) m/z: 310 (M+H)⁺.

(7c)(1R,3S,4S,6R,7R)-7-Benzyloxy-6-t-butyldimethylsilyloxymethyl-3-methoxy-2-oxa-5-aza-bicyclo[2,2,1]heptane-5-carboxylicacid benzyl ester

The compound (152 mg, 0.49 mmol) synthesized in Example 7 (7b) wasdissolved in pyridine (4 mL) and t-butyldimethylsilyl chloride (82 mg,0.54 mmol) was added thereto, followed by stirring of the mixture at 0°C. for 3 hours. After it was confirmed by TLC that the raw material wasno longer present, benzoyl chloride (86 μL, 0.74 mmol) was added and themixture was stirred at 0° C. for 1 hour. After water (20 mL) was addedthereto at 0° C. and the mixture was extracted with ethyl acetate, theorganic layer was washed with saturated brine (20 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 10:1, V/V) to obtain thedesired title compound (218 mg, yield 84%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ −0.24-−0.04 (6H, m), 0.72 (4.5H, s), 0.77(4.5H, s), 3.34 (1.5H, s), 3.38 (1.5H, s), 3.67-3.80 (2H, m), 3.91 (0.5Hm), 4.10 (0.5H, m), 4.40 (0.5H, s), 4.46 (0.5H, m), 4.66 (0.5H, s), 4.69(1H, m), 4.78 (0.5H, m), 5.15 (2H, m), 5.44 (1H, m), 7.39-7.36 (5H, m),7.41 (2H, m), 7.55 (1H, m) 7.95 (2H, m);

MS (FAB) m/z: 528 (M+H)⁺.

(7d)(2R,3R,4R,5R)—N-Benzyloxycarbonyl-3-benzoyl-2,5-dihydroxymethyl-4-hydroxypyrrolidine

The compound (997 mg, 1.89 mmol) synthesized in Example 7 (7c) wasdissolved in trifluoroacetic acid:water (4:1, 12 mL) and the mixture wasstirred at room temperature for 15 minutes. After water (20 mL) wasadded to the reaction mixture at 0° C. and the mixture was extractedwith dichloromethane (30 mL), the organic layer was washed withsaturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine(20 mL) and dried with anhydrous sodium sulfate, followed by distillingoff of the solvent under reduced pressure. The residue was dissolved inethanol (15 mL) and the compound obtained by dissolving sodiumborohydride (35.7 mg, 0.10 mmol) in water (5 mL) was added thereto,followed by stirring of the mixture at 0° C. for 20 minutes. Aftersaturated aqueous ammonium chloride (2 mL) was added to the reactionmixture at 0° C., ethanol was distilled off under reduced pressure.After water (15 mL) was added thereto and the mixture was extracted withethyl acetate (15 mL), the organic layer was washed with saturated brine(15 mL) and dried with anhydrous sodium sulfate, followed by distillingoff of the solvent under reduced pressure. The residue was purifiedusing silica gel flash column chromatography (hexane:ethyl acetate, 2:1,V/V) to obtain the desired title compound (643 mg, yield 85%) as acolorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.60-3.38 (9H, m), 4.98-5.19 (4H, m),7.20-7.30 (5H, m), 7.36 (2H, m), 7.50 (1H, m), 7.89 (2H, d, J=7.3 Hz);

MS (FAB) m/z: 402 (M+H)⁺.

(7e)(2R,3R,4R,5R)—N-Benzyloxycarbonyl-3-hydroxy-2,5-dibenzyloxymethyl-4-benzyloxypyrrolidine

The compound (643 mg, 1.60 mmol) synthesized in Example 7 (7d) wasdissolved in dichloromethane:cyclohexane (1:2, 18 mL) and benzyltricloroacetoimidate (2.7 mL, 14.4 mmol) and trifluoromethanesulfonicacid (29 μL, 0.32 mmol) were added thereto, followed by stirring of themixture at room temperature for 2 hours. After saturated aqueous sodiumhydrogencarbonate (5 mL) was added to the reaction mixture at 0° C. andthe mixture was diluted with ethyl acetate (200 mL), it was washed withwater (30 mL) and saturated brine (30 mL) and dried with anhydroussodium sulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 20:1-10:1, V/V) to obtain 1080 mgof colorless oil. The thus obtained 1080 mg of colorless oil wasdissolved in methanol:tetrahydrofuran (4:1, 25 mL) and potassiumcarbonate (44 mg, 0.32 mmol) was added thereto, followed by stirring ofthe mixture at room temperature for 2.5 hours. After methanol wasdistilled off under reduced pressure, water (15 mL) was added theretoand the mixture was extracted with ethyl acetate (15 mL). The organiclayer was washed with saturated brine (15 mL) and dried with anhydroussodium sulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, V/V) to obtain the desiredtitle compound (715 mg, yield 78%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.40-3.49 (2H, m), 3.62 (1H, dd, J=4.4, 8.8Hz), 3.79-4.12 (4H, m), 4.19 (1H, dd, J=3.7, 10.3 Hz), 4.26-4.61 (6H,m), 5.01 (1H, d, J=16.8 Hz), 5.03 (1H, d, J=16.8 Hz), 5.51 (1H, m),7.15-7.38 (20H, m);

MS (FAB) m/z: 568 (M+H)⁺.

(7f)(2R,3R,4R,5R)-N-Benzyloxycarbonyl-2,5-dibenzyloxymethyl-4-benzyloxypyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (426 mg, 0.49 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (8 mL) and trichloroacetonitrile (0.25mL, 2.45 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (7 μL, 0.05 mmol)were added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (398 mg, 80%) of colorless oil. The compound (248 mg,0.44 mmol) synthesized in Example 7 (7e) was dissolved in diethyl ether(8 mL) and trimethylsilyl trifluoromethanesulfonate (7 μL, 44 μmol) wasadded thereto under a nitrogen atmosphere. A solution of imidate indiethyl ether (5 mL) was added to the reaction mixture and the mixturewas stirred at room temperature for 1.5 hours. After triethylamine (12μL, 88 μmol) was added to the reaction mixture and the solvent wasdistilled off under reduced pressure, it was diluted with ethyl acetate(20 mL) and washed with saturated aqueous sodium hydrogencarbonate (20mL) and saturated brine (20 mL). After the organic layer was dried withanhydrous sodium sulfate, the solvent was distilled off under reducedpressure and the residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 4:1, V/V) to obtain the desiredtitle compound (218 mg, 31%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃): δ 1.23 (3H, d, J=5.9 Hz), 2.92-3.19 (4H, m),3.26-3.73 (13H, m), 3.85 (1H, dd, J=5.1, 5.1 Hz), 3.93 (1H, dd, J=5.1,5.1 Hz), 4.31 (1H, d, J=8.0 Hz), 5.03 (1H, d, J=3.6 Hz);

MS (FAB) m/z: 472 (M+H)⁺.

(7g) (2R,3R,4R,5R)-2,5-Dihydroxymethyl-4-hydroxypyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (218 mg, 0.15 mmol) synthesized in Example 7 (7f) wasdissolved in 1% hydrochloric acid methanol solution (5 mL) and 20%palladium hydroxide-carbon (110 mg) was added thereto, followed bystirring of the mixture under a hydrogen atmosphere for 2 hours. Afterthe catalyst was removed by celite filtration, 28% ammonia water (0.8mL) was added thereto, followed by stirring of the mixture for 10minutes. After the solvent was distilled off under reduced pressure andit was passed through ion exchange resin column with water (30 mL), 1%ammonia water (30 mL) was flowed through. The ammonia water containingthe desired compound was concentrated under reduced pressure and waspurified using silica gel flash column chromatography (ethylacetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired titlecompound (47 mg, 64%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 1.15 (3H, d, J=5.9 Hz), 2.92-3.19 (4H, m),3.26-3.73 (13H, m), 3.85 (1H, dd, J=5.1, 5.1 Hz), 3.93 (1H, dd, J=5.1,5.1 Hz), 4.31 (1H, d, J=88.0 Hz), 5.03 (1H, d, J=3.6 Hz);

MS (FAB) m/z: 472 (M+H)⁺.

Example 8 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-methoxy-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside(Exemplification compound No. 1-354)

(8a) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (2.19 g, 2.37 mmol) synthesized in Example 2 (2c) wasdissolved in N,N-dimethylformamide (45 mL) and sodium hydride (0.12 g,2.75 mmol) was added thereto under ice-cooling, followed by stirring ofthe mixture for 10 minutes. Methyl iodide (0.3 mL, 4.82 mmol) was addedthereto and the mixture was stirred at room temperature for 5 hours.Methanol (5 mL) was added to the reaction mixture under ice-cooling andthe mixture was stirred for 30 minutes. Ethyl acetate (20 mL) was addedthereto and the organic layer was washed with water (20 mL) andsaturated brine (20 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1-5:1, V/V) to obtain the desired titlecompound (1.80 g, yield 81%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.21 (3H, s), 3.30-5.00 (28H, m), 5.10 (1H,m), 5.20 (1H, m), 5.95 (1H, m), 7.20-7.40 (30H, m);

MS (FAB) m/z: 938 (M+H)⁺.

(8b) Allyl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-methoxy-6-deoxy-β-D-glucopyranosyl)-D-glucopyranoside

The compound (1.80 g, 1.92 mmol) synthesized in Example 8 (8a) wasdissolved in methanol (30 mL) and tetrahydrofuran (6 mL) and palladiumchloride (II) (67.4 mg, 0.38 mmol) was added thereto, followed bystirring of the mixture at room temperature for 14 hours. After thereaction mixture was subjected to celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate,5:1-4:1-3:1, V/V) to obtain the desired title compound (1.43 g, yield83%) as colorless amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.20 (3H, s), 3.25-5.00 (27H, m), 5.10 (1H,m), 7.20-7.40 (30H, m);

MS (FAB) m/z: 898 (M+H)⁺.

(8c)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-(benzyloxymethyl)pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-methoxy-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (762.6 mg, 0.85 mmol) synthesized in Example 8 (8b) wasdissolved in methylene chloride (14 mL) and trichloroacetonitrile (0.43mL, 4.29 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 drop) wereadded thereto, followed by stirring of the mixture at room temperaturefor 30 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, 1% triethylamine, V/V) toobtain imidate (567.8 mg, 64%) of colorless oil. The compound (380.8 mg,0.85 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether(13 mL) and trimethylsilyl trifluoromethanesulfonate (8.0 μL, 0.044mmol) was dissolved in diethyl ether (2 mL) under a nitrogen atmosphereand it was added. A solution of imidate (567.8 mg) in diethyl ether (5mL) was added to the reaction mixture and the mixture was stirred atroom temperature for 2 hours. After triethylamine (8.0 μL, 0.057 mmol)was added to the reaction mixture and the solvent was distilled offunder reduced pressure, it was diluted with ethyl acetate (20 mL) andthe mixture was washed with saturated aqueous sodium hydrogencarbonatesolution (20 mL) and saturated brine (20 mL). After the organic layerwas dried with anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure and the residue containing the α,β mixture waspurified using silica gel flash column chromatography (hexane:diethylether, 3:1, V/V) to isolate the desired title compound a form (150.1 mg,13%) thereof as colorless amorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.20 (3H, s), 3.25-5.20 (39H, m), 7.20-7.40(45H, m);

MS (FAB) m/z: 1327 (M+H)⁺.

(8d) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-methoxy-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (150.1 mg, 0.11 mmol) synthesized in Example 8 (8c) wasdissolved in methanol (10 mL) containing 1% aqueous hydrochloric acidsolution and 20% palladium hydroxide-carbon (100 mg) was added thereto,followed by stirring of the mixture under a hydrogen atmosphere for 2hours. After the catalyst was removed by celite filtration, 28% ammoniawater (0.5 mL) was added thereto and the mixture was stirred for 10minutes. After the solvent was distilled off under reduced pressure andthe aqueous solution (100 mL) was subjected to ion exchange resin (Dowex50w×8) column, it was eluted with 1% ammonia water (100 mL). The ammoniawater containing the desired compound was concentrated under reducedpressure and the residue was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) toobtain the desired title compound (49.1 mg, 95%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.00-4.20 (19H, m), 3.27 (3H, s), 4.37 (1H,d, J=8.0 Hz), 4.98 (1H, d, J=3.7 Hz);

MS (FAB) m/z: 472 (M+H)⁺.

Example 9 (2R,3R,4R)-4-Fluoro-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-115)

(9a)(2R,3R,4R)-3-Benzoyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-4-hydroxy-pyrrolidine

The compound (3.37 g, 9.07 mmol) synthesized in Example 1 (1 h) wasdissolved in methylene chloride:cyclohexane (1:2, 180 mL) and benzyltrichloroacetoimidate (2.0 mL, 10.88 mmol) and trifluoromethanesulfonicacid (2.57 mL, 15.3 mmol) were added thereto, followed by stirring ofthe mixture at room temperature for 1 hour. After saturated aqueoussodium hydrogencarbonate solution (20 mL) was added to the reactionmixture at 0° C. and the mixture was diluted with ethyl acetate (200mL), it was washed with water (300 mL) and saturated aqueous sodiumhydrogencarbonate solution (300 mL) and dried with anhydrous sodiumsulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1-2:1, V/V) to obtain 4.71 g ofpale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 3.50-4.20 (4H, m), 4.45-4.80 (3H, m),5.00-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 (1H, m), 7.99 (2H, m);

MS (FAB) m/z: 462 (M+H)⁺.

(9b)(2R,3R,4S)-3-Benzoyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-4-hydroxy-pyrrolidine

The compound (183 mg, 0.40 mmol) synthesized in Example 9 (9a) wasdissolved in methylene chloride (4 mL) and pyridine (96 μL, 1.20 mmol)and trifluoromethanesulfonic acid anhydride (0.10 mL, 0.60 mmol) wereadded thereto, followed by stirring of the mixture at 0° C. for 20minutes. After water (10 mL) was added thereto at 0° C. and the mixturewas extracted with methylene chloride, the organic layer was washed withsaturated brine (10 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 2:1, V/V) to obtain the desired title compound(92 mg, yield 50%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 3.25-4.20 (4H, m), 4.25-4.75 (3H, m),5.10-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 (1H, t, J=7.4 Hz), 7.99 (2H,d, J=8.8 Hz);

MS (FAB) m/z: 462 (M+H)⁺.

(9c)(2R,3R,4R)—N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-pyrrolidine

The compound (980 mg, 2.12 mmol) synthesized in Example 9 (9b) wasdissolved in 1,2-dimethoxyethane (20 mL) and diethylaminosulfurtrifluoride (0.84 mL, 6.36 mmol) was added thereto at −20° C. Thetemperature of the mixture was gradually raised and the mixture wasstirred at 60° C. for 1 hour. After saturated aqueous sodiumhydrogencarbonate solution was added thereto at 0° C. until foaming didnot occur, the mixture was extracted with ethyl acetate and the organiclayer was washed with saturated brine (20 mL) and dried with anhydroussodium sulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, V/V) to obtain a pale yellowoil (545 mg). The thus obtained pale yellow oil (545 mg) was dissolvedin methanol (10 mL) and potassium carbonate (50 mg) was added thereto,followed by stirring of the mixture at room temperature for 20 minutes.After the solvent was distilled off under reduced pressure, water (20mL) was added thereto and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine (20 mL). The solventwas distilled off under reduced pressure and the residue was purifiedusing silica gel flash column chromatography (hexane:ethyl acetate, 2:1,V/V) to obtain the desired title compound (263 mg, yield 34%) as acolorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.10-4.20 (4H, m), 4.25-4.75 (3H, m),4.80-5.20 (5H, m), 7.30-7.45 (10H, m);

MS (FAB) m/z: 360 (M+H)⁺.

(9d)(2R,3R,4R)—N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (657 mg, 0.76 mmol) synthesized in Example 1 (1f) wasdissolved in methylene chloride (12 mL) and trichloroacetonitrile (0.38mL, 3.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (11 μL, 76 μmol)were added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (767 mg, 100%) of colorless oil. The compound (263 mg,0.73 mmol) synthesized in Example 9 (9c) was dissolved in diethyl ether(12 mL) and trimethylsilyl trifluoromethanesulfonate (13 μL, 73 μmol)was added thereto under a nitrogen atmosphere. A solution of imidate indiethyl ether (8 mL) was added to the reaction mixture and the mixturewas stirred at room temperature for 1.5 hours. After triethylamine (20μL, 146 μmol) was added to the reaction mixture and the solvent wasdistilled off under reduced pressure, the residue was diluted with ethylacetate (20 mL) and the mixture was washed with saturated aqueous sodiumhydrogencarbonate (20 mL) and saturated brine (20 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure and the residue was purified using silica gelflash column chromatography (hexane:diethyl ether, 4:1, V/V) to obtainthe desired title compound α isomer (109 mg, 12%) and β isomer (52 mg,6%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.09 (3H, d, J=4.2 Hz), 3.00-5.60 (35H, m),7.10-7.40 (40H, m);

MS (FAB) m/z: 1209 (M+H)⁺.

(9e) (2R,3R,4R)-4-Fluoro-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (109 mg, 90.2 μmol) synthesized in Example 9 (9d) wasdissolved in 1% hydrochloric acid methanol solution (5 mL) and 20%palladium hydroxide-carbon (55 mg) was added thereto, followed bystirring of the mixture under a hydrogen atmosphere for 1 hour. Afterthe catalyst was removed by celite filtration, 28% ammonia water (0.2mL) was added thereto and the mixture was stirred for 10 minutes. Afterthe solvent was distilled off under reduced pressure and it was passedthrough ion exchange resin (Dowex 50w×8) column with water (30 mL), 1%ammonia water (30 mL) was flowed through. The ammonia water containingthe desired compound was concentrated under reduced pressure and theresidue was purified using silica gel flash column chromatography (ethylacetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired titlecompound (26 mg, 65%) as a colorless solid.

¹H NMR (500 MHz, CDCl₃): δ 1.18 (3H, d, J=5.9 Hz), 2.98-3.16 (4H, m),3.47-3.77 (12H, m), 4.11 (1H, dd, J=4.9, 20.5 Hz), 5.02 (1H, m), 5.23(1H, m);

MS (FAB) m/z: 444 (M+H)⁺.

Example 10 (2R,3R,4R)-4-Hydroxy-2-fluoromethyl-pyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-119)

(10a)(2R,3R,4R)-3-Benzoyloxy-N-benzyloxycarbonyl-2-fluoromethyl-4-hydroxy-pyrrolidine

The compound (257 mg, 0.69 mmol) synthesized in Example 1 (1 h) wasdissolved in 1,2-dimethoxyethane (5 mL) and diethylaminosulfurtrifluoride (0.11 mL, 0.83 mmol) was added thereto at −20° C. Thetemperature of the mixture was gradually raised and the mixture wasstirred at 60° C. for 1 hour. After saturated aqueous sodiumhydrogencarbonate solution was added thereto at 0° C. until foaming didnot occur, the mixture was extracted with ethyl acetate (15 mL) and theorganic layer was washed with saturated brine (15 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain acolorless oil (113 mg, 44%).

¹H NMR (400 MHz, CDCl₃): δ 3.50-4.25 (4H, m), 4.50-5.55 (3H, m),5.40-5.60 (2H, m), 7.20-7.50 (7H, m), 7.60 (1H, m), 8.00-8.10 (2H, m);

MS (FAB) m/z: 374 (M+H)⁺.

(10b)(2R,3R,4S)-3-Benzoyloxy-N-benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidine

The compound (344 mg, 0.92 mmol) synthesized in Example 10 (10a) wasdissolved in methylene chloride:cyclohexane (1:2, 10 mL) and benzyltrichloroacetoimidate (0.68 mL, 3.68 mmol) and trifluoromethane sulfonicacid (16 μL, 0.18 mmol) were added thereto, followed by stirring of themixture at room temperature for 4 hours. After saturated aqueous sodiumhydrogencarbonate (1 mL) was added to the reaction mixture at 0° C. andthe mixture was diluted with ethyl acetate (20 mL), the mixture waswashed with water (20 mL) and saturated brine (20 mL) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 8:1-5:1, V/V) to obtain acolorless oil (307 mg, 68%).

¹H NMR (400 MHz, CDCl₃): δ 3.50-5.25 (7H, m), 5.50-5.75 (4H, m),7.20-7.50 (12H, m), 7.60 (1H, m), 8.00-8.10 (2H, m);

MS (FAB) m/z: 464 (M+H)⁺.

(10c)(2R,3R,4S)—N-Benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidine

The compound (307 mg, 0.66 mmol) synthesized in Example 10 (10b) wasdissolved in methanol (6 mL) and potassium carbonate (27 mg, 0.20 mmol)was added thereto, followed by stirring of the mixture at roomtemperature for 2.5 hours. After methanol was distilled off underreduced pressure, water (15 mL) was added thereto and the mixture wasextracted with ethyl acetate (15 mL). The organic layer was washed withsaturated brine (15 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound(176 mg, yield 74%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.35-4.80 (7H, m), 5.50-5.75 (4H, m),7.20-7.50 (10H, m);

MS (FAB) m/z: 360 (M+H)⁺.

(10d)(2R,3R,4R)—N-Benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (398 mg, 0.46 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (8 mL) and trichloroacetonitrile (0.23mL, 2.30 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (7 μL, 0.05 mmol)were added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate of colorless oil. The compound (165 mg, 0.46 mmol)synthesized in Example 10 (10c) was dissolved in diethyl ether (8 mL)and trimethylsilyl trifluoromethanesulfonate (8 μL, 46 μmol) was addedthereto under a nitrogen atmosphere. A solution of imidate in diethylether (4 mL) was added to the reaction mixture and the mixture wasstirred at room temperature for 2.5 hours. After triethylamine (13 μL,92 μmol) was added to the reaction mixture and the solvent was distilledoff under reduced pressure, the residue was diluted with ethyl acetate(15 mL) and the mixture was washed with saturated aqueous sodiumhydrogencarbonate (15 mL) and saturated brine (15 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure and the residue was purified using silica gelflash column chromatography (hexane:diethyl ether, 4:1, V/V) to obtainthe desired title compound (53 mg, 10%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.10 (3H, d, J=4.2 Hz), 3.00-5.60 (35H, m),7.10-7.40 (40H, m);

MS (FAB) m/z: 1209 (M+H)⁺.

(10e) (2R,3R,4R)-4-Hydroxy-2-fluoromethyl-pyrrolidin-3-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (53 mg, 43.9 mmol) synthesized in Example 10 (10d) wasdissolved in 1% hydrochloric acid methanol solution (5 mL) and 20%palladium hydroxide-carbon (30 mg) was added thereto, followed bystirring of the mixture under a hydrogen atmosphere for 3 hours. Afterthe catalyst was removed by celite filtration, 28% ammonia water (0.2mL) was added thereto and the mixture was stirred for 10 minutes. Afterthe solvent was distilled off under reduced pressure and it was passedthrough ion exchange resin column with water (30 mL), 1% ammonia water(30 mL) was flowed through. The ammonia water containing the desiredcompound was concentrated under reduced pressure and the residue waspurified using silica gel flash column chromatography (ethylacetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired titlecompound (1.6 mg, 8%) as a colorless solid.

¹H NMR (500 MHz, CDCl₃): δ 1.18 (3H, d, J=4.0 Hz), 2.98-4.25 (16H, m),4.50 (2H, m), 5.83 (1H, m);

MS (FAB) m/z: 444 (M+H)⁺.

Example 11 (2R,3R,4S)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 1-1)

(11a)(2R,3R,4S)—N-Benzyloxycarbonyl-4-benzyloxy-2-benzyloxymethyl-3-hydroxy-pyrrolidine

The compound (815 mg, 1.77 mmol) synthesized in Example 9 (9b) wasdissolved in dichloromethane:cyclohexane (1:2, 45 mL) andbenzyltrichloroacetoimidate (0.66 mL, 3.54 mmol) andtrifluoromethanesulfonic acid (24 μL, 0.27 mmol) were added thereto,followed by stirring of the mixture at room temperature for 1.5 hours.After saturated aqueous sodium hydrogencarbonate solution (5 mL) wasadded to the reaction mixture at 0° C. and the mixture was diluted withethyl acetate (200 mL), the mixture was washed with water (50 mL) andsaturated aqueous sodium hydrogencarbonate solution (50 mL) and driedwith anhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 4:1, V/V) to obtain a paleyellow oil (866 mg). Thus obtained pale yellow oil (866 mg) wasdissolved in methanol (15 mL) and potassium carbonate (65 mg) was addedthereto, followed by stirring of the mixture at room temperature for 1hour. After the solvent was distilled off under reduced pressure, water(20 mL) was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine (20 mL). Thesolvent was distilled off under reduced pressure and the residue waspurified using silica gel flash column chromatography (hexane:ethylacetate, 5:1-2:1, V/V) to obtain the desired title compound (233 mg,yield 30%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.35-4.25 (6H, m), 4.25-4.70 (4H, m)5.00-5.30 (4H, m), 7.09-7.26 (15H, m);

MS (FAB) m/z: 448 (M+H)⁺.

(11b)(2R,3R,4S)—N-Benzyloxycarbonyl-2-benzyloxymethyl-4-benzyloxy-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (513 mg, 0.59 mmol) synthesized in Example 1 (1f) wasdissolved in methylene chloride (10 mL) and trichloroacetonitrile (0.3mL, 2.95 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (9 μL, 0.06 mmol)were added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (447 mg, 75%) of colorless oil. The compound (233 mg,0.52 mmol) synthesized in Example 11 (11a) was dissolved in diethylether (10 mL) and trimethylsilyl trifluoromethanesulfonate (9 μL, 59μmol) was added thereto under a nitrogen atmosphere. A solution ofimidate in diethyl ether (5 mL) was added to the reaction mixture andthe mixture was stirred at room temperature for 1.5 hours. Aftertriethylamine (16 μL, 118 μmol) was added to the reaction mixture andthe solvent was distilled off under reduced pressure, it was dilutedwith ethyl acetate (20 mL) and the mixture was washed with saturatedaqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL).After the organic layer was dried with anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure and the residue waspurified using silica gel flash column chromatography (hexane:diethylether, 5:1-4:1, V/V) to obtain the desired title compound α isomer (58mg, 8%) and β isomer (51 mg, 7%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.15 (3H, d, J=5.6 Hz), 3.10-5.20 (36H, m),1.15 (1H, d, J=6.3 Hz), 7.20-7.39 (45H, m);

MS (FAB) m/z: 1297 (M+H)⁺.

(11c) (2R,3R,4S)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (58 mg, 44.7 μmol) synthesized in Example 11 (11b) wasdissolved in 1% hydrochloric acid methanol solution (5 mL) and 20%palladium hydroxide-carbon (30 mg) was added thereto, followed bystirring of the mixture under a hydrogen atmosphere for 1.5 hours. Afterthe catalyst was removed by celite filtration, 28% ammonia water (0.2mL) was added thereto and the mixture was stirred for 10 minutes. Afterthe solvent was distilled off under reduced pressure and it was passedthrough ion exchange resin (Dowex 50w×8) column with water (30 mL), 1%ammonia water (30 mL) was flowed through. The ammonia water containingthe desired compound was concentrated under reduced pressure and theresidue was purified using silica gel flash column chromatography (ethylacetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired titlecompound (13 mg, 68%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 1.19 (3H, d, J=4.1 Hz), 2.80-4.60 (17H, m),5.00 (1H, d, J=3.6 Hz), 5.24 (1H, d, J=3.0 Hz);

MS (FAB) m/z: 442 (M+H)⁺.

Example 12 (2R,3R,4R)-2-Hydroxymethyl-3-hydroxy-pyrrolidin-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside) (Exemplificationcompound No. 1-556)

(12a)(2R,3R,4R)—N-Benzyloxycarbonyl-2-benzyloxymethyl-3-hydroxy-pyrrolidin-4-yl2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (607 mg, 0.70 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (10 mL) and trichloroacetonitrile (500μL, 4.98 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (630 mg, 89%) as a yellow oil. The compound (323 mg,0.700 mmol) synthesized in Example 9 (9a) was dissolved in diethyl ether(10 mL) and imidate (630 mg, 0.623 mmol) was added thereto.Trimethylsilyl trifluoromethanesulfonate (6.3 μL, 34.8 μmol) wasdropwise thereto and the mixture was stirred at room temperature for 45minutes. After triethylamine (4 drops) was added to the reactionmixture, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:diethyl ether, 6:1, V/V) to obtain the desired title compound(610 mg, 75%) as a pale yellow oil. Subsequently the pale yellow oil(610 mg, 0.465 mmol) was dissolved in methanol (10 mL) and potassiumcarbonate water (1M, 1 mL, 1 mmol) was added thereto, followed bystirring of the mixture at room temperature for 3 hours. The solvent wasdistilled off under reduced pressure and the residue was purified usingsilica gel flash column chromatography (hexane:diethyl ether, 2:1, V/V)to obtain the desired title compound (280 mg, yield 50%) as a colorlesssolid.

¹H NMR (400 MHz, D₂O): δ 1.19 (3H, d, J=5.8 Hz), 2.83 (1H, brs), 3.12(1H, t, J=9.3 Hz), 3.17-3.23 (1H, m), 3.29-3.37 (2H, m), 3.39-3.45 (2H,m), 3.51 (1H, dd, J=9.76, 2.93 Hz), 3.60 (1H, brt, J=7.8 Hz), 3.72-4.01(7H, m), 4.27-4.56 (6H, m), 4.60-4.63 (2H, m), 4.73-4.75 (4H, brm), 4.78(1H, d, J=10.75 Hz), 4.85 (1H, d, J=10.74 Hz), 4.87 (1H, d, J=9.77 Hz),4.92 (1H, d, J=2.93 Hz), 5.01-5.12 (3H, m), 7.21-7.34 (38H, m), 7.43(2H, d, J=6.83 Hz);

MS (FAB) m/z: 1207 (M+H)⁺.

(12b) (2R,3R,4R)-2-Hydroxymethyl-3-hydroxy-pyrrolidin-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (90 mg, 74.6 μmol) synthesized in Example 12 (12a) wasdissolved in methanol (10 mL) and hydrochloric acid (140 μL) and 20%palladium hydroxide-carbon (90 mg) were added thereto, followed bystirring of the mixture at room temperature under a hydrogen atmospherefor 2 hours. After the celite filtration, ammonia water (5%) was addedthereto until the pH became neutral. The solvent was distilled off underreduced pressure and the residue was purified by ion exchange resin(Dowex 50w×8) column (water-5% ammonia water). Further, it was purifiedusing silica gel flash column chromatography (ethylacetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound(26 mg, 79%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 1.32 (3H, d, J=5.8 Hz), 3.17-3.22 (2H, m),3.30-3.38 (2H, m), 3.44-3.55 (2H, m), 3.60-3.64 (2H, m), 3.74-3.86 (6H,m), 3.92 (1H, brd, J=11.72 Hz), 4.13 (1H, brs), 4.24 (1H, brs), 4.48(1H, d, J=7.81 Hz), 5.11 (1H, d, J=2.93 Hz);

MS (FAB) m/z: 442 (M+H)⁺.

Example 13 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-β-D-glucopyranoside (Exemplificationcompound No. 1-1)

The compound β form (60 mg, 46.3 μmol) synthesized in Example 1 (1j) wasdissolved in methanol (4 mL) and hydrochloric acid (56 μL) and 20%palladium hydroxide-carbon (60 mg) were added thereto, followed bystirring of the mixture at room temperature under a hydrogen atmospherefor 4 hours. After the celite filtration, 18% ammonia water (3 drops)was added thereto and the solvent was distilled off under reducedpressure. The residue was purified by ion exchange resin (Dowex 50w×8)column (water-5% ammonia water). Further, it was purified using silicagel flash column chromatography (ethyl acetate:methanol:water, 3:2:1,V/V) to obtain the desired title compound (10 mg, 49%) as a colorlesssolid.

¹H NMR (400 MHz, D₂O): δ 1.29 (3H, d, J=5.8 Hz), 2.93 (1H, dd, J=11.7,3.6 Hz), 3.15-3.35 (4H, m), 3.51-3.65 (5H, m), 3.74-3.80 (5H, m),3.93-4.00 (2H, m), 4.40 (1H, br, s), 4.56 (1H, d, J=7.3 Hz), 5.34 (1H,br, s);

MS (FAB) m/z: 464 (M+Na)⁺, 442 (M+H)⁺.

Example 14(1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 5-1)

(14a) Methyl4-O-benzoyl-2,3-di-O-benzyl-6-O-p-toluenesulfonyl-α-D-glucopyranoside

Methyl 2,3-di-O-benzyl-6-O-p-toluenesulfonyl-α-D-glucopyranoside (J.Org. Chem., 2001, 66, 5965-5975) (163.9 g, 310 mmol) was dissolved inmethylene chloride (1.5 L) and 4-dimethylaminopyridine (43.5 g, 352mmol) and triethylamine (49.0 mL, 352 mmol) were added thereto. Benzoylchloride (43.2 mL, 372 mmol) was dropwise thereto and the mixture wasstirred at 0° C. for 1 hour. After diluted hydrochloric acid (2N, 500mL) was added to the reaction mixture and the mixture was extracted withmethylene chloride (1 L), the organic layer was washed with saturatedaqueous sodium hydrogencarbonate (1 L) and saturated brine (1 L) anddried with anhydrous sodium sulfate, followed by distilling off of thesolvent under reduced pressure. The residue was purified using silicagel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) toobtain the desired title compound (196 g, yield 99%) as a colorlesssolid.

¹H NMR (400 MHz, CDCl₃): δ 2.34 (3H, s), 3.40 (3H, s), 3.58 (1H, dd,J=9.3, 3.4 Hz), 3.98-4.10 (4H, m), 4.57-4.65 (3H, m), 4.79 (1H, d,J=10.8 Hz), 5.06 (1H, dd, J=9.8, 9.8 Hz), 7.08-7.10 (5H, m), 7.18 (2H,d, J=7.8 Hz), 7.29-7.35 (5H, m), 7.41-7.45 (2H, m), 7.57-7.61 (1H, m),7.67 (2H, d, J=7.8 Hz), 7.89 (2H, d, J=8.8 Hz);

MS (FAB) m/z: 633 (M+H)⁺.

(14b) Methyl4-O-benzoyl-2,3-di-O-benzyl-6-deoxy-6-iode-α-D-glucopyranoside

The compound (196 g, 310 mmol) synthesized in Example 14 (14a) wasdissolved in toluene (2 L) and sodium iodide (235 g, 1.57 mol) and18-crown-6-ether (16.6 g, 62.8 mmol) were added thereto under a nitrogenatmosphere, followed by stirring of the mixture at 100° C. for 2 hours.The reaction mixture was cooled to room temperature and was filtered andthe filtered product was washed with toluene. The filtrate and thewashing liquid were washed with saturated aqueous sodiumhydrogencarbonate (1 L) and saturated brine (1 L) and dried withanhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure to obtain the desired title compound (181 g,yield 99%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.12 (1H, dd, J=11.0, 8.8 Hz), 3.29 (1H, dd,J=11.0, 2.2 Hz), 3.51 (3H, s), 3.64 (1H, dd, J=9.6, 3.7 Hz), 3.82-3.89(1H, m), 4.06 (1H, dd, J=9.6, 8.8 Hz), 4.60-4.68 (3H, m), 4.82 (1H, d,J=11.0 Hz), 4.82 (1H, d, J=12.8 Hz), 5.06 (1H, dd, J=9.5, 9.5 Hz),7.08-7.10 (5H, m), 7.29-7.38 (5H, m), 7.42-7.47 (2H, m), 7.57-7.61 (1H,m), 7.98 (2H, d, J=8.0 Hz);

MS (FAB) m/z: 589 (M+H)⁺.

(14c) 4-O-Benzoyl-2,3-di-O-benzyl-5,6-dideoxy-D-xylo-hex-5-enose oxime

The compound (181 g, 307 mmol) synthesized in Example 14 (14b) wasdissolved in isopropanol (1.5 L) and distilled water (50 mL) and zincpowder (180 g) washed with diluted hydrochloric acid was added thereto,followed by stirring of the mixture at 100° C. for 1 hour. The reactionmixture was subjected to celite filtration, the filtered product waswashed with ethanol and the filtrate and the washing liquid weredistilled off under reduced pressure. The residue was dissolved inethanol (500 mL) and hydroxylamine hydrochloride (42.7 g, 615 mmol) andpyridine (49.7 mL, 615 mmol) were added thereto, followed by stirring ofthe mixture at 80° C. for 40 minutes. The solvent was distilled offunder reduced pressure and the residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 5:1, V/V) to obtainthe desired title compound (126 g, yield 92%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.83 (0.7H, dd, J=5.8, 4.9 Hz), 3.99 (0.3H,dd, J=6.2, 3.9 Hz), 4.23 (0.7H, dd, J=7.8, 4.9 Hz), 4.42 (1H, dd,J=11.8, 3.9 Hz), 4.65 (1H, d, J=11.7 Hz), 4.68-4.76 (3H, m), 4.97 (0.3H,dd, J=5.8, 3.9 Hz), 5.23 (1H, dd, J=10.7, 5.9 Hz), 5.31-5.37 (1H, m),5.78-5.94 (2H, m), 7.20-7.38 (9H, m), 7.40-7.48 (3H, m), 7.53-7.59 (1H,m), 8.00-8.07 (2H, m);

MS (FAB) m/z: 446 (M+H)⁺.

(14d)(3aR,4R,5R,6S,6aR)-4-Benzoyloxy-5,6-dibenzyloxy-hexahydro-cyclopenta[c]isoxasole

The compound (126 g, 282 mmol) synthesized in Example 14 (14c) wasdissolved in toluene (800 mL) and the mixture was stirred at 120° C. for8 hours. The solvent was distilled off under reduced pressure and theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound(59.7 g, yield 48%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 2.83-2.91 (1H, m), 3.45-3.60 (1H, m),3.89-3.95 (2H, m), 4.11-4.18 (1H, m), 4.55 (1H, m), 4.75-4.87 (4H, m),5.01 (1H, dd, J=7.8, 6.8 Hz), 5.09-5.13 (1H, m), 7.22-7.40 (10H, m),7.43-7.47 (2H, m), 7.57-7.61 (1H, m), 7.97-8.00 (2H, m);

MS (FAB) m/z: 446 (M+H)⁺.

(14e)(3aR,4R,5S,6S,6aR)-1-Benzyloxycarbonyl-5,6-dibenzyloxy-4-hydroxy-hexahydro-cyclopenta[c]isoxazole

The compound (59.7 g, 134 mmol) synthesized in Example 14 (14d) wasdissolved in methanol (1 L) and sodium methoxide (10 mL, 49 mmol) wasadded thereto, followed by stirring of the mixture at room temperaturefor 15 minutes. After saturated aqueous ammonium chloride solution (500mL) was added to the reaction mixture at 0° C. and the mixture wasextracted with ethyl acetate (1.5 L), the organic layer was washed withsaturated brine (50 mL). Saturated aqueous sodium hydrogencarbonate (500mL) and benzyloxychloroformate (22.9 mL, 160 mmol) were added to theorganic layer at 0° C. and the mixture was stirred at 0° C. for 1 hour.After the organic layer was washed with saturated brine (500 mL) anddried with anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desiredtitle compound (61.3 g, yield 96%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 2.30 (1H, brd, J=3.7 Hz, OH), 2.91 (1H, ddd,J=8.9, 8.9, 5.7 Hz, H-3a), 3.58 (1H, dd, J=9.0, 5.7 Hz, H-3), 3.73 (1H,dd, J=8.6, 8.4 Hz, H-5), 3.82 (1H, ddd, J=8.9, 8.6, 3.7 Hz, H-4), 3.84(1H, dd, J=8.4, 5.6 Hz, H-6), 3.98 (1H, d, J=9.0 Hz, H-3), 4.54 (1H, d,J=11.3 Hz), 4.54 (1H, dd, J=8.9, 5.6 Hz, H-6a), 4.63 (1H, d, J=11.7 Hz),4.84 (1H, d, J=11.3 Hz), 4.87 (1H, d, J=11.7 Hz), 5.20 (1H, d, J=12.1Hz), 5.27 (1H, d, J=12.1 Hz), 7.23-7.40 (15H, m).

MS (FAB) m/z: 476 (M+H)⁺.

(14f)(3aR,4R,5R,6S,6aR)-1-Benzyloxycarbonyl-5,6-dibenzyloxy-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(6-deoxy-2,3,4-tri-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (215 mg, 0.248 mmol) synthesized in Example 1 (1f) wasdissolved in methylene chloride (5 mL) and trichloroacetonitrile (460μL, 4.61 mmol) and 1,8-diazabicyclo 5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (250 mg, 99%) as a yellow oil. The compound (100 mg, 0.21mmol) synthesized in Example 14 (14e) was dissolved in diethyl ether (10mL) and imidate (250 mg, 0.248 mmol) was added thereto. Trimethylsilyltrifluoromethanesulfonate (3.8 μL, 0.021 mmol) was added dropwisethereto and the mixture was stirred at room temperature for 45 minutes.After triethylamine (4 drops) was added to the reaction mixture, thesolvent was distilled off under reduced pressure. The residue waspurified using silica gel flash column chromatography (hexane:diethylether, 2:1, V/V) to obtain the desired title compound (55 mg, 17%) as apale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.15 (3H, d, J=6.8 Hz), 3.01-3.12 (2H, m),3.14 (1H, dd, J=9.8, 3.9 Hz), 3.50-3.62 (3H, m), 3.64-3.80 (2H, m),3.80-3.96 (5H, m), 3.99-4.10 (2H, m), 4.43 (1H, d, J=11.7 Hz), 4.47 (1H,d, J=11.7 Hz), 4.50-4.62 (7H, m), 4.68-4.93 (8H, m), 5.06 (1H, d, J=11.7Hz), 5.18-5.29 (3H, m), 5.61 (1H, d, J=3.9 Hz), 7.05-7.41 (45H, m);

MS (FAB) m/z: 1324 (M+H)⁺.

(14g)(1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-α-D-glucopyranosyl)-Cα-D-glucopyranoside

The compound (53 mg, 40.4 μmol) synthesized in Example 14 (14f) wasdissolved in methanol (10 mL) and hydrochloric acid (10 μL) and 20%palladium hydroxide-carbon (53 mg) were added thereto, followed bystirring of the mixture at room temperature under a hydrogen atmospherefor 4 hours. After celite filtration, the solvent was distilled offunder reduced pressure and the residue was purified by ion exchangeresin (Dowex 50w×8) column (water-5% ammonia water). Further, it waspurified using silica gel flash column chromatography (ethylacetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound(5 mg, 26%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 1.18 (3H, d, J=6.8 Hz), 2.00-2.08 (1H, m),2.15-2.22 (1H, m), 3.03-3.09 (1H, m), 3.16-3.22 (1H, m), 3.45-3.57 (5H,m), 3.58-3.78 (8H, m), 3.81-3.89 (3H, m), 5.10 (1H, d, J=2.9 Hz), 5.23(1H, d, J=2.9 Hz);

MS (FAB) m/z: 472 (M+H)⁺.

Example 15(1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 5-1)

(15a)(3aR,4R,5R,6S,6aR)-1-Benzyloxycarbonyl-5,6-dibenzyloxy-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (1.0 g, 1.15 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (30 mL) and trichloroacetonitrile (460μL, 4.61 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (970 mg, 84%) as a yellow oil. The compound (508 mg, 1.06mmol) synthesized in Example 14 (14e) was dissolved in diethyl ether (20mL) and imidate (970 mg, 0.97 mmol) was added thereto. Trimethylsilyltrifluoromethanesulfonate (17 μL, 0.097 mmol) was added dropwise theretoand the mixture was stirred at room temperature for 45 minutes. Aftertriethylamine (4 drops) was added to the reaction mixture, the solventwas distilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:diethyl ether, 1:1, V/V)to obtain the desired title compound (125 mg, 9%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.22 (3H, d, J=6.8 Hz), 2.81-2.87 (1H, m),3.15 (1H, dd, J=9.8, 8.7 Hz), 3.19-3.24 (1H, m), 3.28-3.36 (2H, m),3.40-3.45 (1H, m), 3.52 (1H, dd, J=8.8, 3.9 Hz), 3.55-3.59 (1H, m), 3.75(1H, dd, J=10.7, 3.9 Hz), 3.79-3.84 (2H, m), 3.86-3.91 (1H, m),3.93-4.01 (2H, m), 4.31 (1H, d, J=11.7 Hz), 4.35 (1H, d, J=7.8 Hz), 4.50(1H, d, J=11.7 Hz), 4.52-4.59 (2H, m), 4.60-4.64 (3H, m), 4.70-4.87(10H, m), 4.89 (1H, d, J=12.7 Hz), 5.00 (1H, d, J=10.7 Hz), 5.07 (1H, d,J=3.9 Hz), 5.21 (1H, d, J=11.7 Hz), 5.28 (1H, d, J=12.7 Hz), 7.10-7.43(45H, m)

MS (FAB) m/z: 1324 (M+H)⁺.

(15b)(1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (115 mg, 86.8 μmol) synthesized in Example 15 (15a) wasdissolved in methanol (20 mL) and ethyl acetate (1 mL) and hydrochloricacid (10 μL) and 20% palladium hydroxide-carbon (115 mg) were addedthereto, followed by stirring of the mixture at room temperature under ahydrogen atmosphere for 4 hours. After celite filtration, the solventwas distilled off under reduced pressure and the residue was purified byion exchange resin (Dowex 50w×8) column (water-5% ammonia water).Further, it was purified using silica gel flash column chromatography(ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired titlecompound (30 mg, 73%) as a colorless amorphous.

[α]D20 +60.9 (c 0.11, H₂O);

¹H NMR (400 MHz, D₂O): δ 1.21 (3H, d, J=6.8 Hz), 2.17-2.25 (1H, m),3.05-3.10 (1H, m), 3.18-3.27 (2H, m), 3.30-3.92 (14H, m), 4.38 (1H, d,J=7.8 Hz), 5.08-5.10 (1H, m);

MS (FAB) m/z: 472 (M+H)⁺.

Example 16(1R,2S,3R,4R,5R)-1-(2-Hydroxy-1-hydroxymethyl-ethylamino)-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 5-22)

(16a)(3aR,4R,5R,6S,6aR)-4-Benzoyloxy-5,6-dibenzyloxy-1-(1,3-dihydroxyprop-2-yl)-hexahydro-cyclopenta[c]isoxazole

The compound (3.07 g, 6.89 mmol) synthesized in Example 14 (14d) wasdissolved in methanol (10 mL) and tetrahydrofuran (10 mL) and1,3-dihydroxyacetone (1.86 g, 20.7 mmol) and acetic acid (1 mL) wereadded thereto, followed by stirring of the mixture at 70° C. for 30minutes. Sodium cyanoborohydride (1.30 g, 20.67 mmol) was added theretoand the mixture was stirred at 70° C. for 10 hours. The solvent wasdistilled off under reduced pressure and the residue was purified usingsilica gel flash column chromatography (methylene chloride:methanol,20:1, V/V) to obtain the desired title compound (1.20 g, yield 33%) as acolorless solid.

¹H NMR (400 MHz, CDCl₃): δ 2.35 (1H, dd, J=6.8, 4.9 Hz), 2.39 (1H, t,J=5.9 Hz), 2.77-2.82 (1H, m), 2.93-3.00 (1H, m), 3.74-3.84 (3H, m),3.88-3.94 (1H, m), 3.96-4.08 (3H, m), 4.21-4.26 (2H, m), 4.74-4.86 (4H,m), 5.05 (1H, d, J=7.8, 5.9 Hz), 7.26-7.38 (10H, m), 7.45-7.50 (2H, m),7.59-7.64 (1H, m), 7.98-8.02 (2H, m);

MS (FAB) m/z: 520 (M+H)⁺.

(16b)(3aR,4R,5S,6S,6aR)-5,6-Dibenzyloxy-1-(2,2-dimethyl-[1,3]dioxan-5-yl)-4-hydroxy-hexahydro-cyclopenta[c]isoxazole

The compound (1.20 g, 2.31 mmol) synthesized in Example 16 (16a) wasdissolved in acetone (30 mL) and 2,2-dimethoxy propane (2.27 mL, 18.5mmol) and p-toluenesulfonic acid monohydrate (660 mg, 3.47 mmol) wereadded thereto, followed by stirring of the mixture at room temperaturefor 15 minutes. After saturated aqueous sodium hydrogencarbonate (50 mL)was added to the reaction mixture at 0° C. and the mixture was extractedwith ethyl acetate (50 mL), the organic layer was washed with saturatedbrine (50 mL). The solvent was distilled off under reduced pressure andthe residue was dissolved in methanol. Sodium methoxide (0.4 mL, 1.96mmol) was added thereto and the mixture was stirred at room temperaturefor 20 minutes. After saturated aqueous ammonium chloride (50 mL) wasadded to the reaction mixture at 0° C. and the mixture was extractedwith ethyl acetate (50 mL), the organic layer was washed with saturatedbrine (50 mL) and dried with anhydrous sodium sulfate, followed bydistilling off of the solvent under reduced pressure. The residue waspurified using silica gel flash column chromatography (hexane:ethylacetate, 1:1, V/V) to obtain the desired title compound (840 mg, yield80%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 1.39 (3H, s), 1.47 (3H, s), 2.06 (1H, d,J=3.9 Hz), 2.85-2.96 (2H, m), 3.49 (1H, dd, J=9.8, 6.8 Hz), 3.67-3.72(1H, m), 3.75-3.85 (6H, m), 3.89-3.97 (2H, m), 4.67 (1H, d, J=11.7 Hz),4.68 (1H, d, J=11.7 Hz), 4.76 (1H, d, J=11.7 Hz), 4.85 (1H, d, J=11.7Hz), 7.26-7.38 (10H, m);

MS (FAB) m/z 456: (M+H)⁺.

(16c)(3aR,4R,5S,6S,6aR)-5,6-Dibenzyloxy-1-(2,2-dimethyl-[1,3]dioxan-5-yl)-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (600 mg, 0.692 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (20 mL) and trichloroacetonitrile (277μL, 2.76 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (550 mg, 80%) as a yellow oil. The compound (230 mg,0.501 mmol) synthesized in Example 16 (16b) was dissolved in diethylether (10 mL) and imidate (550 mg, 0.551 mmol) was added thereto.Trimethylsilyl trifluoromethanesulfonate (45 μL, 0.250 mmol) was addeddropwise thereto and the mixture was stirred at room temperature for 45minutes. After triethylamine (4 drops) was added to the reactionmixture, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound(140 mg, 20%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.22 (3H, d, J=5.8 Hz), 1.43 (3H, s) 1.49(3H, s), 2.70-2.80 (2H, m), 3.11-3.17 (1H, m), 3.19-3.27 (1H, m),3.30-3.54 (6H, m), 3.61-3.95 (12H, m), 4.34 (1H, d, J=11.7 Hz), 4.38(1H, d, J=7.3 Hz), 4.52 (1H, d, J=12.5 Hz), 4.58-4.73 (5H, m), 4.73-4.90(8H, m), 5.00 (1H, d, J=3.7 Hz), 5.03 (1H, d, J=11.0 Hz), 7.17-7.38(38H, m), 7.43-7.47 (2H, m).

MS (FAB) m/z: 1304 (M+H)⁺.

(16d)(1R,2S,3R,4R,5R)-1-(2-Hydroxy-1-hydroxymethyl-ethylamino)-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (146 mg, 113 μmol) synthesized in Example 16 (16c) wasdissolved in acetic acid (10 mL) and distilled water (2.5 mL) and themixture was stirred at 50° C. for 1 hour. The solvent was distilled offunder reduced pressure and the residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 1:1, v/V) to obtaindiol (128 mg, 101 μmol) as a colorless crystal. The diol (118 mg, 93.3μmol) was dissolved in methanol (20 mL) and ethyl acetate (1 mL) andhydrochloric acid (30 μL) and 20% palladium hydroxide-carbon (118 mg)were added thereto, followed by stirring of the mixture at roomtemperature under a hydrogen atmosphere for 4 hours. After celitefiltration, the solvent was distilled off under reduced pressure and theresidue was purified by ion exchange resin (Dowex 50w×8) column(water-5% ammonia water). Further, it was purified using silica gelflash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V)to obtain the desired title compound (43 mg, 84%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 1.32 (3H, d, J=6.8 Hz), 2.34-2.41 (1H, m),2.88-2.94 (1H, m), 3.16-3.22 (1H, m), 3.29-3.38 (2H, m), 3.42-3.50 (1H,m), 3.49-3.97 (16H, m), 4.48 (1H, d, J=7.8 Hz), 5.18 (1H, d, J=7.8 Hz);

¹³C NMR (100 MHz, D₂O): δ 16.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6,61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5, 81.9,97.8, 102.7;

MS (FAB) m/z: 546 (M+H)⁺.

Example 17(1R,2S,3S,4R,5R)-1-Amino-2-fluoro-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 5-9)

(17a) Methyl 2-deoxy-2-fluoro-D-glucopyranoside

1,3,4,6-tetra-O-Acetyl-2-deoxy-2-fluoro-β-D-glucopyranose (Carbohydr.Res., 153, 1986, 168-170) (13.4 g, 38.3 mmol) was dissolved in methanol(150 mL) and Dowex 50w×8 (19 g) was added thereto, followed by stirringof the mixture at 80° C. for 12 hours. The reaction mixture wassubjected to celite filtration and the filtered product was washed withmethanol. The filtrate and the washing liquid were combined anddistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (methylene chloride:methanol,10:1-5:1, V/V) to obtain the desired title compound (3.37 g, yield 45%)as a colorless solid.

¹H NMR (400 MHz, CD3OD): δ 3.32-3.36 (1H, m), 3.43 (1.5H, s), 3.52-3.64(2H, m), 3.54 (1.5H, s), 3.65-3.70 (1H, m), 3.80-3.92 (2.5H, m),4.16-4.29 (0.5H, m), 4.43 (0.5H, dd, J=7.8, 2.9 Hz), 4.88 (0.5H, d,J=3.9 Hz).

MS (FAB) m/z: 197 (M+H)⁺.

(17b) Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-D-glucopyranoside

The compound (3.5 g, 17.9 mmol) synthesized in Example 17 (17a) wasdissolved in dimethylformamide (70 mL) and benzaldehyde dimethylacetal(3.75 mL, 25.0 mmol) and p-toluenesulfonic acid monohydrate (170 mg,0.892 mmol) were added thereto, followed by stirring of the mixture at50° C. under reduced pressure for 2 hours. Triethylamine (2 mL) wasadded to the reaction mixture and the solvent was distilled off underreduced pressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 3:1, V/V) to obtain the desiredtitle product (3.36 g, yield 66%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.42-3.58 (1H, m), 3.48 (2H, s), 3.60 (1H,s), 3.70-3.90 (1.33H, m), 3.98-4.08 (0.66H, m), 4.16-4.40 (2H, m),4.48-4.54 (1H, m), 4.94 (0.66H, d, J=4.4 Hz), 5.02-5.06 (0.33H, m),5.52-5.54 (1H, m), 7.36-7.41 (3H, m), 7.46-7.51 (2H, m);

MS (FAB) m/z: 285 (M+H)⁺.

(17c) Methyl4-O-benzoyl-3-O-benzyl-2-deoxy-2-fluoro-6-O-p-toluenesulfonyl-D-glucopyranoside

The compound (3.36 g, 11.8 mmol) synthesized in Example 17 (17b) wasdissolved in dimethylformamide (50 mL) and sodium hydride (741 mg, 17.7mmol) was added thereto under a nitrogen atmosphere, followed bystirring of the mixture at room temperature for 30 minutes. The reactionmixture was ice-cooled and benzyl bromide (1.68 mL, 14.1 mmol) was addedthereto, followed by stirring of the mixture at room temperature for 2hours. After saturated aqueous ammonium chloride solution (50 mL) wasadded to the reaction mixture at 0° C. and the mixture was extractedwith ethyl acetate (100 mL), the organic layer was washed with saturatedbrine (100 mL) and dried with anhydrous sodium sulfate, followed bydistilling off of the solvent under reduced pressure. Acetic acid (16mL) and distilled water (4 mL) were added to the residue and the mixturewas stirred at 60° C. for 3 hours. The solvent was distilled off underreduced pressure and the reaction mixture was azeotroped with toluene.The residue was dissolved in pyridine (10 mL) and p-toluenesulfonic acidchloride (1.75 g, 9.20 mmol) and 4-dimethylaminopyridine (101 mg, 0.83mmol) were added thereto under ice-cooling, followed by stirring of themixture at room temperature for 6 hours. The reaction mixture wasice-cooled and diluted hydrochloric acid (2N, 80 mL) was added thereto.After the mixture was extracted with ethyl acetate (100 mL), the organiclayer was washed with saturated aqueous sodium hydrogencarbonate (200mL) and saturated brine (200 mL) and dried with anhydrous sodiumsulfate, followed by distilling off of the solvent under reducedpressure. The residue was dissolved in methylene chloride (40 mL) and4-dimethylaminopyridine (1.28 g, 10.5 mmol), benzoyl chloride (1.30 mL,11.2 mmol) and triethylamine (1.46 mL, 10.5 mmol) were added theretounder ice-cooling, followed by stirring of the mixture at 0° C. for 3hours. The reaction mixture was ice-cooled and diluted hydrochloric acid(2N, 80 mL) was added thereto. After the mixture was extracted withmethylene chloride (100 mL), the organic layer was washed with saturatedaqueous sodium hydrogencarbonate (200 mL) and saturated brine (100 mL)and dried with anhydrous sodium sulfate, followed by distilling off ofthe solvent under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V)to obtain the desired title compound (4.16 g, yield 65%) as a colorlesssolid.

¹H NMR (400 MHz, CDCl₃): δ 2.35 ( 3/2H, s), 2.36 ( 3/2H, s), 3.47 (3/2H, s), 3.55 ( 3/2H, s), 3.79-3.88 (1H, m), 4.01-4.15 (3H, m),4.28-4.62 (3.5H, m), 4.77 (1H, dd, J=11.7, 5.1 Hz), 4.91 (0.5H, d, J=4.4Hz), 5.05-5.12 (1H, m), 7.06-7.10 (5H, m), 7.18-7.22 (2H, m), 7.42-7.48(2H, m), 7.58-7.65 (1H, m), 7.66-7.71 (2H, m), 7.89-7.93 (2H, m);

MS (FAB) m/z: 545 (M+H)⁺.

(17d) Methyl4-O-benzoyl-3-O-benzyl-2,6-dideoxy-2-fluoro-6-iode-D-glucopyranoside

The compound (3.83 g, 7.03 mmol) synthesized in Example 17 (17c) wasdissolved in toluene (120 mL) and sodium iodide (5.27 g, 39.2 mmol) and18-crown-6-ether (370 mg, 1.40 mmol) were added thereto under a nitrogenatmosphere, followed by stirring of the mixture at 100° C. for 2 hours.The reaction mixture was cooled to room temperature and filtered and thefiltered product was washed with toluene. The filtrate and the washingliquid were washed with saturated aqueous sodium hydrogencarbonate (100mL) and saturated brine (100 mL) and dried with anhydrous sodiumsulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, V/V) to obtain the desiredtitle compound (3.38 g, yield 96%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.12-3.21 (1H, m), 3.27-3.32 (1H, m)3.57-3.62 (1H, m), 3.58 ( 3/2H, s), 3.65 ( 3/2H, s), 3.82-3.91 (1H, m),4.38-4.68 ( 5/2H, m), 4.79 (1H, dd, J=11.7, 6.8 Hz), 4.99 (½H, dd, J=3.9Hz), 5.06-5.13 (1H, m), 7.07-7.18 (5H, m), 7.43-7.48 (2H, m), 7.59-7.64(1H, m), 7.95-8.00 (2H, m);

MS (FAB) m/z: 501 (M+H)⁺.

(17e) 4-O-Benzoyl-3-O-benzyl-2-fluoro-2,5,6-trideoxy-D-xylo-hex-5-enoseoxime

The compound (3.37 g, 6.74 mmol) synthesized in Example 17 (17d) wasdissolved in isopropanol (40 mL) and distilled water (1.3 mL) and zincpowder (4 g) washed with diluted hydrochloric acid was added thereto,followed by stirring of the mixture at 100° C. for 1 hour. The reactionmixture was subjected to celite filtration, the filtered product waswashed with ethanol and the filtrate and the washing liquid weredistilled off under reduced pressure. The residue was dissolved inethanol (80 mL) and hydroxylamine hydrochloride (1.18 g, 17.1 mmol) andpyridine (1.38 mL, 17.1 mmol) were added thereto, followed by stirringof the mixture at 60° C. for 40 minutes. The solvent was distilled offunder reduced pressure and the residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 5:1, V/V) to obtainthe desired title compound (1.31 g, yield 54%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 3.87-3.94 (0.7H, m), 4.13-4.22 (0.3H, m),4.64-4.82 (2H, m), 5.22 (0.7H, ddd, J=46.9, 6.8, 4.9 Hz), 5.34-5.55 (2H,m), 5.75-5.88 (1.3H, m), 5.98-6.07 (1H, m), 7.24-7.62 (8H, m), 8.03-8.08(2H, m);

MS (FAB) m/z: 358 (M+H)⁺.

(17f)(3aR,4R,5S,6S,6aR)-4-Benzoyloxy-5-benzyloxy-6-fluoro-hexahydro-cyclopenta[c]isoxazole

The compound (1.31 g, 3.66 mmol) synthesized in Example 17 (17e) wasdissolved in toluene (30 mL) and the mixture was stirred at 120° C. for8 hours. The solvent was distilled off under reduced pressure and theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound(965 mg, yield 74%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 2.91-2.98 (1H, m), 3.50-3.58 (1H, m),4.00-4.10 (1H, m), 4.21-4.28 (1H, m), 4.54 (1H, brd, J=7.8 Hz), 4.72(1H, d, J=12.7 Hz), 4.83 (1H, d, J=12.7 Hz), 4.84 (1H, ddd, J=52.7, 7.8,5.8 Hz), 4.98-5.02 (1H, m), 5.11-5.15 (1H, m), 7.28-7.36 (5H, m),7.45-7.49 (2H, m), 7.59-7.63 (1H, m), 7.97-8.00 (2H, m);

MS (FAB) m/z 358: (M+H)⁺.

(17g)(3aR,4R,5S,6S,6aR)-5-Benzyloxy-1-benzyloxycarbonyl-6-fluoro-4-hydroxy-hexahydro-cyclopenta[c]isoxazole

The compound (950 mg, 2.66 mmol) synthesized in Example 17 (17f) wasdissolved in methanol (10 mL) and sodium methoxide (270 μL, 1.30 mmol)was added thereto, followed by stirring of the mixture at roomtemperature for 15 minutes. After saturated aqueous ammonium chloridesolution (50 mL) was added to the reaction mixture at 0° C. and themixture was extracted with ethyl acetate (50 mL), the organic layer waswashed with saturated brine (50 mL) and dried with anhydrous sodiumsulfate, followed by distilling off of the solvent under reducedpressure. The residue was dissolved in ethyl acetate (100 mL) andsaturated aqueous sodium hydrogencarbonate (50 mL) and benzyloxychloroformate (570 μL, 4.00 mmol) were added thereto at 0° C.,followed by stirring of the mixture at 0° C. for 1 hour. The organiclayer was washed with saturated brine (50 mL) and dried with anhydroussodium sulfate, followed by distilling off of the solvent under reducedpressure. The residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desiredtitle compound (1.00 g, yield 97%) as a colorless solid.

¹H NMR (400 MHz, CDCl₃): δ 2.29 (1H, brd, J=3.3 Hz, OH), 2.92-2.99 (1H,m, H-3a), 3.60 (1H, dd, J=9.0, 5.8 Hz, H-3), 3.82-3.91 (2H, m, H-5,H-4), 3.98 (1H, d, J=8.8 Hz, H-3), 4.61 (1H, d, J=12.7 Hz, CH2Ph),4.62-4.70 (1H, m, H-6a), 4.72-4.76 (½H, m, H-6), 4.84 (1H, d, J=12.7 Hz,CH2Ph), 4.82-4.86 (½H, m, H-6) 5.21 (2H, s), 7.23-7.40 (10H, m);

MS (FAB) m/z: 388 (M+H)⁺.

(17h)(3aR,4R,5S,6S,6aR)-5-Benzyloxy-1-benzyloxycarbonyl-6-fluoro-hexahydro-cyclopenta[c]isoxazol-4-yl2,3,6-tri-O-benzyl-4-O-(6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl)-O-D-glucopyranoside

The compound (840 mg, 0.969 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (10 mL) and trichloroacetonitrile (460μL, 4.61 mmol) and 1,8-diazabicyclo 5.4.0]-7-undecene (2 drops) wereadded thereto, followed by stirring of the mixture at room temperaturefor 40 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (830 mg, 85%) as a yellow oil. The compound (300 mg,0.756 mmol) synthesized in Example 17 (17g) was dissolved in diethylether (15 mL) and imidate (830 mg, 0.832 mmol) was added thereto.Trimethylsilyl trifluoromethanesulfonate (13 μL, 0.0756 mmol) was addeddropwise thereto and the mixture was stirred at room temperature for 45minutes. After triethylamine (4 drops) was added to the reactionmixture, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:diethyl ether, 2:1, V/V) to obtain the desired title compound(86 mg, 9%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H, d, J=5.9 Hz), 2.87-2.94 (1H, m),3.10-3.16 (1H, m), 3.19-3.24 (1H, m), 3.28-3.38 (3H, m), 3.42-3.46 (1H,m), 3.51 (1H, dd, J=9.8, 3.9 Hz), 3.55-3.59 (1H, m), 3.74 (1H, dd,J=10.7, 3.9 Hz), 3.79-3.84 (2H, m), 3.84-3.89 (1H, m), 3.94 (1H, d,J=9.8 Hz), 4.00-4.06 (1H, m), 4.31 (1H, d, J=12.7 Hz), 4.35 (1H, d,J=7.8 Hz), 4.49 (1H, d, J=12.7 Hz), 4.58-4.88 (13H, m), 5.01 (1H, d,J=10.8 Hz), 5.05 (1H, d, J=3.9 Hz), 5.18-5.26 (2H, m), 7.15-7.43 (40H,m);

MS (FAB) m/z: 1236 (M+H)⁺.

(17i)(1R,2S,3S,4R,5R)-1-Amino-2-fluoro-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside

The compound (85 mg, 68.8 μmol) synthesized in Example 17 (17h) wasdissolved in methanol (20 mL) and ethyl acetate (1 mL) and hydrochloricacid (30 μL) and 20% palladium hydroxide-carbon (85 mg) were addedthereto, followed by stirring of the mixture at room temperature under ahydrogen atmosphere for 4 hours. After celite filtration, the solventwas distilled off under reduced pressure and the residue was purified byion exchange resin (Dowex 50w×8) column (water-5% ammonia water).Further, it was purified using silica gel flash column chromatography(ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired titlecompound (28 mg, 86%) as colorless amorphous matter.

¹H NMR (400 MHz, D₂O): δ 1.21 (3H, d, J=5.9 Hz), 2.23-2.30 (1H, m),3.04-3.10 (1H, m), 3.18-3.25 (2H, m), 3.28-3.61 (6H, m), 3.64-3.80 (5H,m), 3.86-3.91 (1H, m), 4.11-4.18 (1H, m), 4.37 (1H, d, J=8.8 Hz),4.41-4.46 (½H, m), 4.52-4.57 (½H, m), 5.06-5.08 (1H, m);

¹³C NMR (100 MHz, D₂O): δ 16.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6,61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5, 81.9,97.8, 102.7;

MS (FAB) m/z: 474 (M+H)⁺.

Example 18(2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside (Exemplificationcompound No. 3-1)

(18a)1,2-O-Benzyl-4-deoxy-3-O-formyl-4-trifluoroacetamido-α-D-arabinoside

2-O-Benzyl-4-deoxy-3-O-formyl-4-trifluoroacetamido-D-arabinoside (Chem.Pharm. Bull., 1991, 39, 2807-2812) (0.80 g, 2.20 mmol) was dissolved inmethylene chloride (50 mL) and benzyl trichloroacetoimidate (0.82 mL,4.40 mmol) and trifluoromethanesulfonic acid (40 μL, 0.22 mmol) wereadded thereto, followed by stirring of the mixture at room temperaturefor 3 hours. After saturated aqueous sodium hydrogencarbonate (30 mL)was added to the reaction mixture at 0° C. and the mixture was dilutedwith ethyl acetate (100 mL), the mixture was washed with water (50 mL)and saturated brine (50 mL) and dried with anhydrous sodium sulfate,followed by distilling off of the solvent under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1, V/V) to obtain the desired title compound(0.73 g, yield 74%) as pale yellow amorphous matter.

¹H NMR (CDCl₃) δ: 3.55 (1H, dd, J=12.5, 2.2 Hz), 3.63 (1H, dd, J=10.3,3.7 Hz), 4.13 (1H, d, J=13.9 Hz), 4.50 (1H, d, J=11.0 Hz), 4.53 (1H, d,J=12.5 Hz), 4.61 (1H, d, J=11.7 Hz), 4.62 (1H, br, s), 4.75 (1H, d,J=12.5 Hz), 4.90 (1H, d, J=2.9 Hz), 5.44 (1H, dd, J=10.3, 4.4 Hz), 6.69(1H, d, J=7.33 Hz), 7.13-7.38 (10H, m), 8.00 (1H, s);

MS (FAB) m/z: 476 (M+Na)⁺.

(18b) 1,2-di-O-Benzyl-4-deoxy-4-trifluoroacetamido-α-D-arabinoside

The compound (0.73 g, 1.61 mmol) synthesized in Example 18 (18a) wasdissolved in methanol (30 mL) and water (5 mL) and potassiumhydrogencarbonate (1.00 g, 10.0 mmol) was added thereto, followed bystirring of the mixture at room temperature for 15 hours. Ethyl acetate(50 mL) was added thereto and the organic layer was washed withsaturated brine (20 mL). After it was dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1, V/V) to obtain the desired title compound(205 mg, yield 41%) as colorless amorphous matter.

¹H NMR (CDCl₃) δ: 2.84 (1H, d, J=2.2 Hz), 3.44 (1H, dd, J=9.5, 2.9 Hz),3.76 (1H, dd, J=12.5, 1.5 Hz), 3.92 (1H, dd, J=12.5, 1.5 Hz), 4.20-4.28(2H, m), 4.47 (1H, d, J=11.7 Hz), 5.53 (2H, s), 4.72 (1H, d, J=12.5 Hz),4.91 (1H, d, J=3.7 Hz), 6.67 (1H, br, d, J=5.86 Hz), 7.12-7.38 (10H, m);

MS (FAB) m/z: 426 (M+H)⁺, 448 (M+Na)⁺.

(18c)1,2-di-O-Benzyl-4-deoxy-4-trifluoroacetamido-3-O-{2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranosyl}-α-D-arabinoside

The compound (0.70 g, 0.81 mmol) synthesized in Example 2 (2f) wasdissolved in methylene chloride (20 mL) and trichloroacetonitrile (1.00mL, 10.0 mmol) and 2 drops of 1,8-diazabicyclo[5.4.0]-7-undecene wereadded thereto, followed by stirring of the mixture at room temperaturefor 30 minutes. After the solvent was distilled off under reducedpressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 5:1, 1% triethylamine, V/V) toobtain imidate (0.75 g, 92%) of colorless oil. The compound (205 mg,0.48 mmol) synthesized in Example 18 (18b) and imidate (0.75 g, 0.74mmol) were dissolved in diethyl ether (30 mL) and trimethylsilyltrifluoromethanesulfonate (8.7 μL, 0.074 mmol) was added thereto under anitrogen atmosphere, followed by stirring of the mixture at roomtemperature for 3 hours. After triethylamine (0.1 mL) was added to thereaction mixture and the solvent was distilled off under reducedpressure, the residue was diluted with ethyl acetate (30 mL) and themixture was washed with saturated aqueous sodium hydrogencarbonate (20mL) and saturated brine (20 mL). After the organic layer was dried withanhydrous sodium sulfate, the solvent was distilled off under reducedpressure and the residue was purified using silica gel flash columnchromatography (hexane:diethyl ether, 3:1, V/V) to obtain the desiredtitle compound (185 mg, 31%) and its β isomer (250 mg, 41%) as colorlessamorphous matter.

¹H NMR (CDCl₃) δ: 1.17 (3H, d, J=5.9 Hz), 3.12 (1H, t, J=9.5 Hz),3.19-3.25 (1H, m), 3.36 (1H, t, J=9.5 Hz), 3.44-3.50 (2H, m), 3.54-3.64(3H, m), 3.75 (1H, t, J=9.5 Hz), 3.81-3.98 (4H, m), 4.19 (1H, dd, J=8.8,4.4 Hz), 4.35-4.39 (3H, m), 4.45 (1H, d, J=111.7 Hz), 4.49-4.54 (3H, m),4.59-4.61 (2H, m), 4.67-4.80 (6H, m), 4.84 (1H, d, J=11.0 Hz), 4.90 (1H,d, J=1.0 Hz), 4.94 (1H, d, J=111.7 Hz), 5.02 (1H, d, J=111.0 Hz), 5.18(1H, d, J=3.7 Hz), 6.88 (1H, br, d, J=7.3 Hz), 7.10-7.40 (40H, m);

MS (FAB) m/z: 1296 (M+Na)⁺.

(18d)4-Deoxy-4-trifluoroacetamido-3-O-{4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranosyl}-D-arabinoside

The compound (180 mg, 0.14 mmol) synthesized in Example 18 (18c) wasdissolved in methanol (10 mL) and 20% palladium hydroxide-carbon (120mg) was added thereto, followed by stirring of the mixture under ahydrogen atmosphere for 3 hours. After the catalyst was removed bycelite filtration, the solvent was distilled off under reduced pressure.The residue was purified using silica gel flash column chromatography(ethyl acetate:methanol, 4:1, V/V) to obtain the desired title compound(69 mg, 88.5%) as a colorless solid.

¹H NMR (D₂O) δ: 1.32 (3H, d, J=5.9 Hz), 3.19 (1H, t, J=9.5 Hz),3.30-3.34 (2H, m), 3.46 (1H, t, J=9.5 Hz), 3.52 (1H, br, t, J=7.4 HZ),3.59-3.67 (3H, m), 3.72-3.88 (3H, m), 3.97-4.07 (2H, m), 4.19-4.29 (1H,m), 4.48 (1H, d, J=88.0 Hz), 4.58-4.66 (2H, m), 5.24 (1H, br, s);

MS (FAB) m/z: 576 (M+Na)⁺.

(18e) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside

The compound (47 mg, 0.085 mmol) synthesized in Example 18 (18d) wasdissolved in water (10 mL) and ion exchange resin Dowex-1×4 (OH—) (3.0g) was added thereto, followed by stirring of the mixture at roomtemperature for 1.5 hours. The ion exchange resin was removed and thesolvent was distilled off under reduced pressure. The residue waspurified using silica gel flash column chromatography(chloroform:methanol:water, 6:4:1, V/V) to obtain the desired titlecompound (8.0 mg, yield 21.4%) as colorless amorphous matter.

¹H NMR (D₂O) δ: 1.32 (3H, d, J=5.9 Hz), 3.16-3.21 (1H, m), 3.31-3.33(1H, m), 3.45-3.52 (2H, m), 3.63-3.69 (2H, m), 3.80-3.96 (5H, m), 4.08(1H, br, s), 4.25 (1H, d, J=4.9 Hz), 4.49 (1H, d, J=6.8 Hz), 4.94 (1H,d, J=4.9 Hz), 5.17 (1H, d, J=4.0 Hz), 7.68 (1H, br, s);

MS (FAB) m/z: 462 (M+Na)⁺.

Example 19 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-glucopyranoside(Exemplification compound No. 1-547)

(19a)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl4-O-acetyl-2,3,6-tri-O-benzyl-α-D-glucopyranoside

4-O-Acetyl-2,3,6-tri-O-benzyl-glucopyranoside (Agric. Biol. Chem, 1986,50, 2261-2272) (2.21 g, 4.49 mmol) was dissolved in methylene chloride(45 mL) and trichloroacetonitrile (2.3 mL, 22.44 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (65 μL, 0.44 mmol) were addedthereto, followed by stirring of the mixture at room temperature for 1hour. After the solvent was distilled off under reduced pressure, theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 2:1, 1% triethylamine, V/V) to obtain imidate(2.06 g, 72.0%) as a yellow oil. The compound (2.00 g, 4.47 mmol)synthesized in Example 1 (1i) was dissolved in diethyl ether (100 mL)and imidate (2.06 g, 3.23 mmol) was added thereto. A solution oftrimethylsilyl trifluoromethanesulfonate (40 μL, 0.22 mmol) in diethylether (2 mL) was added dropwise thereto and the mixture was stirred atroom temperature for 2 hours. After triethylamine (50 μL) was added tothe reaction mixture and the solvent was distilled off under reducedpressure, the residue was diluted with ethyl acetate (20 mL) and themixture was washed with saturated aqueous sodium hydrogencarbonate (20mL) and saturated brine (10 mL). After the organic layer was dried withanhydrous sodium sulfate, the solvent was distilled off under reducedpressure and the residue containing the α, β mixture was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 5:1, V/V)to isolate the desired title compound α form (1.93 g, 46.6%) thereof asa colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.82 (3H, s), 3.20-5.20 (26H, m), 7.10-7.40(30H, m);

MS (FAB) m/z: 922 (M+H)⁺.

(19b)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-α-D-glucopyranoside

The compound (1.57 g, 1.70 mmol) synthesized in Example 19 (19a) wasdissolved in methanol (30 mL) and potassium carbonate (235 mg, 1.70mmol) was added thereto, followed by stirring of the mixture at roomtemperature for 14 hours. The reaction mixture was diluted with ethylacetate (10 mL) and the mixture was washed with saturated aqueous sodiumhydrogencarbonate (10 mL) and saturated brine (10 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure. The residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtainthe desired title compound (1.41 g, 94.0%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.40-5.20 (26H, m), 7.10-7.40 (30H, m);

MS (FAB) m/z: 880 (M+H)⁺.

(19c) Allyl2,3,6-O-tri-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (4.0 g, 10.46 mmol) synthesized in Example 2 (2a) wasdissolved in pyridine (30 mL) and benzoyl chloride (12.1 mL, 104.24mmol) was added thereto under ice-cooling, followed by stirring of themixture at room temperature for 14 hours. The reaction mixture waspoured to 10% aqueous hydrochloric acid solution (20 mL) and methylchloride (20 mL) and the organic layer was washed with 10% aqueoushydrochloric acid solution (20 mL), saturated aqueous sodiumhydrogencarbonate solution (20 mL) and saturated brine (20 mL) and driedwith anhydrous sodium sulfate, followed by distilling off of the solventunder reduced pressure. The residue was purified using silica gel flashcolumn chromatography (hexane:ethyl acetate, 5:1-5:2, V/V) to obtain thedesired title compound (8.10 g, yield 70%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 3.71-4.27 (6H, m), 4.44-4.51 (1H, m),4.58-4.63 (1H, m), 4.72 (1H, d, J=6.4 Hz), 4.93-5.81 (10H, m), 7.17-8.11(35H, m);

MS (FAB) m/z: 1111 (M+H)⁺.

(19d)2,3,6-O-tri-Benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-D-glucopyranoside

The compound (8.10 g, 7.29 mmol) synthesized in Example 19 (19c) wasdissolved in methanol (75 mL) and tetrahydrofuran (15 mL) and palladiumchloride (II) (258 mg, 1.45 mmol) was added thereto, followed bystirring of the mixture at room temperature for 14 hours. After thereaction mixture was subjected to celite filtration, the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (hexane:ethyl acetate, 3:1-2:1,V/V) to obtain the desired title compound (5.10 g, yield 66%) as a paleyellow solid.

¹H NMR (400 MHz, CDCl₃): δ 2.96-3.13 (1H, m), 3.79-3.92 (2H, m),4.05-4.25 (2H, m), 4.33-4.40 (1H, m), 4.47-4.50 (1H, m), 4.60-4.63 (1H,m), 4.89-6.15 (7H, m), 7.21-8.01 (35H, m);

MS (FAB) m/z: 1071 (M+H)⁺.

(19e)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-{2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-glucopyranoside

The compound (414.4 mg, 0.39 mmol) synthesized in Example 19 (19d) wasdissolved in methylene chloride (8 mL) and trichloroacetonitrile (200μL, 1.99 mmol) and 1,8-diazabicyclo 5.4.0]-7-undecene (6 μL, 0.04 mmol)were added thereto, followed by stirring of the mixture at roomtemperature for 1 hour. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 2:1, 1% triethylamine, V/V) toobtain imidate (255.1 mg, 53.8%) as colorless amorphous matter. Thecompound (185.3 mg, 0.21 mmol) synthesized in Example 19 (19b) wasdissolved in diethyl ether (8 mL) and imidate (225.1 mg, 0.21 mmol) wasadded thereto. A solution of trimethylsilyl trifluoromethanesulfonate(38 μL, 0.21 mmol) in diethyl ether (2 mL) was added dropwise theretoand the mixture was stirred at room temperature for 2 hours. Aftertriethylamine (35 μL) was added to the reaction mixture and the solventwas distilled off under reduced pressure, the residue was diluted withethyl acetate (10 mL) and washed with saturated aqueous sodiumhydrogencarbonate (10 mL) and saturated brine (10 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure. The residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) toisolate the desired title compound (295.8 mg, 72.9%) as colorlessamorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.20-5.60 (40H, m), 7.10-7.40 (65H, m);

MS (FAB) m/z: 1932 (M+H)⁺.

(19f)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-glucopyranoside

The compound (295.8 mg, 0.15 mmol) synthesized in Example 19 (19e) wasdissolved in methanol (6 mL) and potassium carbonate (20 mg, 0.14 mmol)was added thereto, followed by stirring of the mixture at roomtemperature for 6 hours. The reaction mixture was diluted with ethylacetate (10 mL) and washed with saturated aqueous sodiumhydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture wasneutralized with methanol-hydrochloric acid and the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (methylene chloride:methanol,30:1-20:1-10:1, V/V) to obtain the desired title compound (100.7 mg,55.8%) as a colorless solid.

¹H NMR (400 MHz, CD3OD): δ 3.20-5.60 (40H, m), 7.10-7.40 (30H, m);

MS (FAB) m/z: 1204 (M+H)⁺.

(19g) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-glucopyranoside

The compound (100.7 mg, 0.084 mmol) synthesized in Example 19 (19f) wasdissolved in methanol (10 mL) and 36% hydrochloric acid (280 μL) andpalladium hydroxide (100 mg) were added thereto, followed by stirring ofthe mixture at room temperature under a hydrogen atmosphere for 4 hours.After celite filtration, 18% ammonia water (1 mL) was added thereto andthe solvent was distilled off under reduced pressure. The residue waspurified by ion exchange resin (Dowex 50w×8) column (water—1% ammoniawater). Further, it was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) toobtain the desired title compound (10.0 mg, 19.2%) as a colorless solid.

¹H NMR (400 MHz, D₂O): δ 3.00-3.95 (25H, m), 4.38 (1H, d, J=8.1 Hz),4.42 (1H, d, J=8.0 Hz), 5.00 (1H, d, J=2.6 Hz);

MS (FAB) m/z: 620 (M+H)⁺.

Example 20 (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-galactopyranoside(Exemplification compound No. 1-547)

(20a)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranoside

4-O-Acetyl-2,3,6-O-tri-benzyl-D-galactopyranoside (BCSJ, 1989, 62,3549-3566) (1.60 g, 3.25 mmol) was dissolved in methylene chloride (30mL) and trichloroacetonitrile (1.6 mL, 15.96 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (50 μL, 0.33 mmol) were addedthereto, followed by stirring of the mixture at room temperature for 1hour. After the solvent was distilled off under reduced pressure, theresidue was purified using silica gel flash column chromatography(hexane:ethyl acetate, 6:1, 1% triethylamine, V/V) to obtain imidate(1.37 g, 66%) as a yellow oil. The compound (0.96 g, 2.01 mmol)synthesized in Example 1 (1i) was dissolved in diethyl ether (50 mL) andimidate (1.37 g, 2.15 mmol) was added thereto. A solution oftrimethylsilyl trifluoromethanesulfonate (20 μL, 0.11 mmol) in diethylether (2 mL) was added dropwise thereto, followed by stirring of themixture at room temperature for 2 hours. After triethylamine (10 μL) wasadded to the reaction mixture and the solvent was distilled off underreduced pressure, the residue was diluted with ethyl acetate (20 mL) andthe mixture was washed with saturated aqueous sodium hydrogencarbonate(20 mL) and saturated brine (10 mL). After the organic layer was driedwith anhydrous sodium sulfate, the solvent was distilled off underreduced pressure and the residue containing the α,β mixture was purifiedusing silica gel flash column chromatography (hexane:ethyl acetate,6:1-4:1, V/V) to isolate the desired title compound α isomer (0.98 g,50%) thereof as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 2.02 (3H, s), 5.15-3.38 (25H, m), 5.61 (1H,m), 7.16-7.35 (30H, m);

MS (FAB) m/z: 922 (M+H)⁺.

(20b)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-α-D-galactopyranoside

The compound (0.98 g, 1.06 mmol) synthesized in Example 20 (20a) wasdissolved in methanol (20 mL) and potassium carbonate (147 mg, 1.06mmol) was added thereto, followed by stirring of the mixture at roomtemperature for 14 hours. The reaction mixture was diluted with ethylacetate (10 mL) and washed with saturated aqueous sodiumhydrogencarbonate (10 mL) and saturated brine (10 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure. The residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 4:1, V/V) to obtainthe desired title compound (772.4 mg, 83%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 2.70-2.81 (1H, m), 3.46-5.15 (26H, m),7.15-7.37 (30H, m);

MS (FAB) m/z: 880 (M+H)⁺.

(20c)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-{2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-galactopyranoside

The compound (516.8 mg, 0.48 mmol) synthesized in Example 20 (20b) wasdissolved in methylene chloride (10 mL) and trichloroacetonitrile (240μL, 2.39 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (7.5 μL, 0.05mmol) were added thereto, followed by stirring of the mixture at roomtemperature for 1 hour. After the solvent was distilled off underreduced pressure, the residue was purified using silica gel flash columnchromatography (hexane:ethyl acetate, 4:1, 1% triethylamine, V/V) toobtain imidate (376.9 mg, 65%) as colorless amorphous matter. Thecompound (270.0 mg, 0.31 mmol) synthesized in Example 20 (20b) wasdissolved in diethyl ether (15 mL) and imidate (376.9 mg, 0.31 mmol) wasadded thereto. A solution of trimethylsilyl trifluoromethanesulfonate(56 μL, 0.31 mmol) in diethyl ether (2 mL) was added dropwise theretoand the mixture was stirred at room temperature for 2 hours. Aftertriethylamine (50 μL) was added to the reaction mixture and the solventwas distilled off under reduced pressure, the residue was diluted withethyl acetate (20 mL) and washed with saturated aqueous sodiumhydrogencarbonate (20 mL) and saturated brine (10 mL). After the organiclayer was dried with anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure. The residue was purified using silica gelflash column chromatography (hexane:ethyl acetate, 4:1-3:1, v/v) toisolate the desired title compound (390.8 mg, 65%) as colorlessamorphous matter.

¹H NMR (400 MHz, CDCl₃): δ 3.20-5.70 (40H, m), 7.10-7.40 (65H, m);

MS (FAB) m/z: 1932 (M+H)⁺.

(20d)(2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl2,3,6-tri-O-benzyl-4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-galactopyranoside

The compound (390.8 mg, 0.20 mmol) synthesized in Example 20 (20c) wasdissolved in methanol (8 mL) and potassium carbonate (27.6 mg, 0.20mmol) was added thereto, followed by stirring of the mixture at roomtemperature for 6 hours. The reaction mixture was diluted with ethylacetate (10 mL) and washed with saturated aqueous sodiumhydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture wasneutralized with methanol-hydrochloric acid and the solvent wasdistilled off under reduced pressure. The residue was purified usingsilica gel flash column chromatography (methylene chloride:methanol,30:1-20:1-10:1, V/V) to obtain the desired title compound (146.5 mg,61%) as a colorless solid.

¹H NMR (400 MHz, CD3OD): δ 1.13 3.20-4.70 (37H, m), 4.97 (1H, d, J=3.6Hz), 5.07 (2H, s), 7.23-7.39 (30H, m);

MS (FAB) m/z: 1226 (M+Na)⁺.

(20e) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl4-O-{4-O-(β-D-glucopyranosyl)-β-D-glucopyranosyl}-α-D-galactopyranoside

The compound (146.5 mg, 0.12 mmol) synthesized in Example 20 (20d) wasdissolved in methanol (15 mL) and 36% hydrochloric acid (420 μL) andpalladium hydroxide (150 mg) were added thereto, followed by stirring ofthe mixture at room temperature under a hydrogen atmosphere for 4 hours.After celite filtration, 18% ammonia water (1 mL) was added thereto, thesolvent was distilled off under reduced pressure and the residue waspurified by ion exchange resin (Dowex 50w×8) column (water—1% ammoniawater). Further, it was purified using silica gel flash columnchromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) toobtain acetate (23.6 mg, 32%) of the desired title compound as acolorless solid.

¹H NMR (400 MHz, D₂O): δ 3.17-3.87 (22H, m), 4.01 (1H, s), 4.11 (1H, s),4.36 (1H, m), 4.38 (1H, d, J=8.0 Hz), 4.56 (1H, d, J=8.0 Hz), 5.04 (1H,s);

MS (FAB) m/z: 620 (M+H)⁺.

Test Example 1 α-Amylase Inhibitory Action

(1) Preparation of Human α-Amylase Solution

“Caribzyme AMY” (International Reagents) was used for the humanpancreatic α-amylase (HPA). Purified water was added to the commerciallyavailable HPA and dissolved to a concentration of 200 IU/l to prepare anα-amylase solution. The activity of the α-amylase was measured using acommercially available α-amylase assay reagent (“Neo-Amylase TestDaiichi”, Daiichi Pure Chemicals).

(2) Preparation of Inhibitory Solutions

Each test compound was prepared with distilled water to a finalconcentration of 0.1 to 30 μg/ml, respectively.

(3) Measurement of Human α-Amylase Inhibitory Activity of InhibitorySolutions

3.78 to 3.9 ml of distilled water and 0 to 120 μl of inhibitory solutionwere added to 100 μl of HPA solution and adjusted to a total volume of 4ml. After incubating for 10 minutes at 37° C., a blue starch tablet(“Neo-Amylase Test Daiichi”, Daiichi Pure Chemicals) was added followedby stirring for about 10 seconds with a mixer and heating for 30 minutesat 37° C. Subsequently, 1.0 ml of 0.5 N aqueous sodium hydroxidesolution was added followed by stirring to stop the reaction, afterwhich the mixture was centrifuged (1,500 G, 5 minutes) and theabsorbance of the resulting supernatant was measured at 620 nm. Amixture to which inhibitory solution had not been added was used as acontrol. In addition, distilled water was added instead of α-amylase foruse as a blank. The inhibition rate was calculated according to thefollowing formula, and the final concentration of test compound requiredto inhibit the activity of the HPA solution by 50% (μg/ml) was taken tobe the IC50 value. Those values are shown in Table 6.Inhibition rate(%)=[1−{(Absorbance of control)−(absorbance ofblank)}/{(absorbance when inhibitor added)−(absorbance of blank)}]×100

TABLE 6 Example No. IC50 (μg/ml) 1 7 × 10⁻¹ 2 2 × 10⁻¹ 3 4 × 10⁻¹ 4 3 ×10⁻¹ 5 7 7 4 8 4 × 10⁻¹ 9 3 × 10 11 1 × 10 13 4 14 1 15 6 × 10⁻¹ 17 3 ×10 18 2 × 10⁻³ 19 6 × 10⁻¹

It was found from Table 6 that compounds of the present invention havesuperior α-amylase inhibitory action.

Test Example 2 Postprandial Hyperglycemia Inhibitory Action

(1) Test Animals

Commercially available normal mice (ddY mice, males, age 8 weeks at thetime of testing, supplied by Japan SLC).

(2) Experimental Methods and Results

For the dose group, a test compound and commercially availablecornstarch were mixed well with 0.5% carboxymethyl cellulose to preparea suspension that was orally administered at 0.3 mg (test compound)/2 g(cornstarch)/kg (body weight) to five mice that had been fasted inadvance for 20 hours. The control group was administered with a similarsuspension in the same manner with the exception of not containing thetest compound.

Blood samples were collected from a tail vein of the mice before dosingand at 0.5, 1, 2 and 3 hours after dosing followed by measurement ofblood glucose levels and calculation of the inhibition rate (%)according to the following formula from the area under the curve (AUC)of the increase in blood glucose levels (area under the curve of thechange in increases in blood glucose levels, mg/dl×hr). Blood glucoselevels were measured using a blood glucose analyzer (Glucoloader GXT, A& T).Inhibition rate(%)=[1−(dose group AUC/control group blood glucoseincrease AUC)]×100

TABLE 7 Example No. Inhibition Rate (%) 2 64

According to Table 7, compounds of the present invention were determinedto have superior action in inhibiting increases in blood glucose levels.Thus, compounds of the present invention are considered to be useful aspostprandial hyperglycemia therapeutic agents.

Test Example 3 Blood Glucose Lowering Action

(1) Test Animals

Commercially available, genetically obese diabetic mice (C57BL/KsJ-db/dbmice, males, age 16 weeks at the time of testing, supplied by CleaJapan).

(2) Experimental Methods and Results

A test compound was mixed into a refined laboratory animal diet(carbohydrate content: 65.95% (w/w), Oriental Yeast) to a test compoundconcentration of 0.005% (w/w) and allowed to be freely ingested bydiabetic mice for 1 week in groups of 5 mice per group. A control groupwas allowed similar unrestricted access to the same feed with theexception of not containing the test compound.

Blood glucose levels were measured before the start of dosing and oneweek after the start of dosing. Blood samples were collected from a tailvein and blood glucose levels were measured using a blood glucoseanalyzer (Glucoloader GXT, A & T) to calculate the blood glucoselowering rate (%) according to the following formula.Blood glucose lowering rate(%)=[1−(compound dose group blood glucoselevel/control group blood glucose level)]×100

TABLE 8 Example No. Blood Glucose Lowering Rate (%) 2 47

According to Table 8, compounds of the present invention were determinedto have superior blood glucose lowering action. Thus, compounds of thepresent invention are considered to be useful as diabetes mellitustherapeutic agents.

Preparation Examples

(1) Capsules Compound of Example 1  10 mg Lactose 110 mg Cornstarch  58mg Magnesium stearate  2 mg Total 180 mg

Powders of each of the ingredients listed above are mixed well andpassed through a 60 mesh sieve (the sieve mesh is based on the Tylermesh). 180 mg of the resulting powder is weighed out and filled intogelatin capsules (No. 3) to prepare capsule preparations.

(2) Tablets Compound of Example 1 10 mg Lactose 85 mg Cornstarch 34 mgCrystalline cellulose 20 mg Magnesium stearate  1 mg Total 150 mg 

Powders of each of the ingredients listed above are mixed well andcompressed and molded into tablets having a weight of 150 mg each. Thesetablets may be coated with sugar or a film as necessary.

(3) Granules Compound of Example 1  10 mg Lactose 839 mg Cornstarch 150mg Hydroxypropyl cellulose  1 mg Total 1000 mg 

Powders of each of the ingredients listed above are mixed well, wettedpurified water and granulated with a basket-type granulator followed bydrying to obtain granules.

INDUSTRIAL APPLICABILITY

Compounds of the present invention in the form of a noveloligosaccharide derivative, its pharmacologically acceptable salts andits pharmacologically acceptable esters demonstrate superior α-amylaseinhibitory action, blood glucose lowering action and lipid loweringaction, and are useful as therapeutic drugs and/or preventive drugs forhyperglycemia, postprandial hyperglycemia, impaired glucose tolerance,diabetes mellitus, obesity, hyperlipemia, fatty liver, hepatomegaly,diabetic complications, neuropathy, arteriosclerosis, cataract ordiabetic nephropathy (and preferably as therapeutic drugs and/orpreventive drugs for hyperglycemia or diabetes mellitus).

1. A compound represented by the general formula (I):

wherein A represents the general formula (A3):

wherein R¹ and R² are the same or different, and each represent a C1-C6alkyl group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6haloalkyl group, R³, R⁴, R⁵ and R⁶ are the same or different, and eachrepresent a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkylgroup, C1-C6 haloalkyl group, amino group which amino group mayoptionally be substituted with one or two C1-C6 alkyl groups or C1-C6hydroxyalkyl groups, hydroxyl group, hydrogen atom or halogen atom, andn represents an integer of 1 or 2; or a pharmacologically acceptablesalt thereof.
 2. The compound according to claim 1, wherein R¹ and R²are the same or different and each represent a C1-C3 alkyl group,hydroxymethyl group, C1-C3 alkoxymethyl group or C1-C3 haloalkyl group;or a pharmacologically acceptable salt thereof.
 3. The compoundaccording to claim 1, wherein R³, R⁴, R⁵ and R⁶ are the same ordifferent and each represent a C1-C3 alkyl group, C1-C3 hydroxyalkylgroup, C1-C3 haloalkyl group, amino group which amino group mayoptionally be substituted with one or two C1-C6 hydroxyalkyl groups,hydroxyl group, hydrogen atom or halogen atom; or a pharmacologicallyacceptable salt thereof.
 4. The compound according to claim 1, whereinsaid compound is(1R,2S,3R,4R,5R)-1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl4-O-(6-deoxy-α-D-glucopyranosyl)-α-D-glucopyranoside; or apharmacologically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising the compound or pharmacologically acceptable saltthereof according to claim 1 or claim 4, and further comprising apharmaceutically acceptable adjuvant or carrier.
 6. An α-amylaseinhibitor comprising the compound or pharmacologically acceptable saltthereof according to claim 1 or claim 4, and further comprising apharmaceutically acceptable adjuvant or carrier.
 7. A hypoglycemic agentcomprising the compound or pharmacologically acceptable salt thereofaccording to claim 1 or claim 4, and further comprising apharmaceutically acceptable adjuvant or carrier.
 8. A pharmaceuticalcomposition for treating hyperglycemia, postprandial hyperglycemia, ordiabetes mellitus, comprising the compound or pharmacologicallyacceptable salt thereof according to claim 1 or claim 4, and furthercomprising a pharmaceutically acceptable adjuvant or carrier.
 9. Amethod of treating diabetes mellitus, which comprises administering apharmacologically effective amount of the compound or pharmacologicallyacceptable salt thereof according to claim 1 or claim 4 to awarm-blooded animal in need thereof.